June 7, 2004 Update On Alzheimer's Disease What has happened in Alzheimer's research in the ten years since President Ronald Reagan was diagnosed with the brain destroying disease? There are several medications that are very modestly helpful in treating the disease but progress is being made in the basic understanding of the underlying causes and therefore in potential effective treatments. The big question that enters everyone's mind who has a relative with Alzheimer's, for example: "Is it hereditary?" Researchers typically divide Alzheimer's into early-onset or late-onset forms, depending on whether the disease is diagnosed before or after age 65. Early-onset disease accounts for a minority of cases, and most of these are more common in certain families, suggesting a strong genetic component. Genetic research in families with inherited Alzheimer's have led to identification of several gene mutations that can cause early-onset disease. For the larger group of late-onset patients, individual genes do not appear to be at fault. More likely, normal variations in the structures of many genes combines with the environment to cause the disease. Environment in this context is a broad category that includes everything from viruses and bacteria to diet, toxins, educational achievement, or life events--and begins at conception. Studying twins is valuable way to assess the genetic component of a disease. "Because we know that identical twins share all their genes in common and fraternal twins have 1/2 their genes in common, we can use this information to quantify how important genes are," says Nancy Pedersen, Ph.D., of the Karolinska Institute in "The added advantage of twins is that they are the same age, and we don't have problems with waiting until other family members have passed the age at risk for the disease," says Pedersen. Several earlier twin studies suggested that even among late-onset cases of Alzheimer's, the contribution of genes was higher than that of the environment, perhaps as high as 75%. But these studies were not set up to specifically look at very old subjects. She and her colleagues studied 662 pairs of twins between the ages of 52 and 98 years. Her report was published in the on-line edition of Annals of Neurology. During the 5 years, on average, of follow-up, 5.8% of the study participants were diagnosed with Alzheimer's, a figure consistent with other research. Of the identical twin pairs where one of the siblings developed Alzheimer's, the other twin also developed the disease in 32.2% of the cases. Among the nonidentical twins, this figure was only 8.7%. Using statistical modeling techniques, the researchers were able to estimate that half or more of the susceptibility to Alzheimer's disease in later life is attributable to environmental causes. Restoring Connections Synapses are the minute space between two neurons or between a neuron and an organ across which nerve impulses are chemically transmitted. By discovering one of the first mechanisms through which brain synapses are dismantled, an MIT neuroscientist sheds new light on how our brains eliminate connections between neurons. The work was reported on Science magazine’s Science Express web site. Co-author Morgan Sheng, the Menicon Professor of Neuroscience in MIT’s Sheng, a Howard Hughes Medical Institute investigator, studies the structural and functional connections in the brain and how they are altered during development and by experience. Synapses are eliminated all the time, especially in young developing brains, to balance out new synapses that form in response to experience and learning. The number of synapses in the adult brain stays pretty constant; there is less turnover than in the young brain. But exactly how the brain accomplishes this paring process is not well-understood. Serum-inducible kinase (SNK) is involved in cell cycle control in dividing cells. In the brain, cells do not divide, but SNK has taken on the function of degrading the proteins that make up synapses. By inhibiting SNK, Pak and Sheng made neurons grow more synapses than normal. “When we used a molecular trick to inhibit function of the SNK protein kinase, neurons sprouted a lot more synapses. It’s doable in a culture dish in the laboratory, but whether it’s doable in the living brain, I’m not sure,” Sheng says TREATMENTS Plug It In Genetically modified tissue placed directly into the brains of patients with Alzheimer’s disease is being tested to determine whether such a procedure can delay brain cell loss associated with the disease. The experiment is proving to increase metabolic activity in the brain, according to preliminary findings reported at a recent Though the Phase I study (earliest using humans) conducted at the University of California, San Diego (UCSD) was small and designed to test safety and toxicity, the subjects appeared to show some early indications of reduction in the advancement of their disease, according to the study’s principal investigator Mark Tuszynski, M.D., Ph.D., professor of neurosciences at the UCSD School of Medicine. "These results are intriguing," said Tuszynski. "If these effects are borne out in larger, controlled trials, this could be a significant advance over existing therapies for Alzheimer's disease." Eight volunteers diagnosed with early-stage Alzheimer’s disease participated in this study, with the first surgery performed in April 2001 at UCSD’s John M. and With the last human subject now more than a year beyond surgery, no adverse effects from the NGF-producing implants have been detected in the subjects, an indication that the biological therapy is itself safe and well-tolerated. Vitamin E Can Vitamin E help prevent Alzheimer's? Vitamin E, a well-known antioxidant, has been used to treat Alzheimer’s disease, but with mixed results, especially in patients with advanced symptoms. A risk factor for Alzheimer’s is oxidative stress, a clinical condition characterized by an excessive production of reactive chemicals in the brain, which can damage important regions of this organ. Domenico Praticò, M.D., assistant professor of pharmacology at the University of Pennsylvania School of Medicine, and colleagues tested the idea that timing of vitamin E supplementation for treating Alzheimer’s might be an important factor in its effectiveness. They found that vitamin E given to young transgenic mice before the formation of telltale plaques reduces by up to half the levels of amyloid deposited in the brain over time compared to aged mice on the same regimen. This study appears in a recent edition of The FASEB Journal. “Our findings indicate that an antioxidant is important to cure or prevent disease only if given at a very early stage,” says Praticò. “If given when the disease is already established the chances of a positive effect are very small.” The immediate implications of these findings are simple, especially for patients diagnosed with mild cognitive impairment (MCI), a possible precursor to Alzheimer’s: Start taking vitamin E early. “They will benefit the most,” says Praticò. “ Considering that up to 50 percent of patients with MCI will develop Alzheimer’s within four years, and the fact that recent epidemiological studies have clearly shown that intake of antioxidants, in particular vitamin E, lowers the risk of Alzheimer’s, MCI patients will be the most appropriate target for this therapy.” Sage An ancient folk remedy may also help treat Alzheimer's. Sage (Salvia officinalis) was named for its medical virtues (salvia means "to save") by the Roman naturalist Pliny the Elder in the first century AD. It was said to help memory and quicken the senses. Today's researchers have found that the herb does have antioxidant and anti-inflammatory properties. Two small studies--one with 19 healthy young adults, the other with 24--were conducted by neuroscientists from the Medicinal Plant Research Centre at the Universities of Northumbria and The studies were done because the British researchers found that sage inhibits the enzyme acetylcholinesterase, which breaks down the neurotransmitter acetylcholine. Acetylcholine levels are known to fall in people who have Alzheimer's disease. The researchers are in the process of trying to find alternatives to current Alzheimer's drugs, which can have unpleasant side effects. Herbalists are using one teaspoon of the spice from the spice rack in one cup of boiling water. It is steeped for 5 minutes, strained and then drunk. It supposedly improves memory function if taken before exams or business presentations. For more information about brain research and function, check: Brain Workout: Easy Ways to Power Up Your Memory, Sensory Perception, and Intelligence by Arthur Winter, MD and Ruth Winter, MS. Music, Exercise and Your Brain It's no secret that exercise improves mood, but new research suggests that working out to music may give exercisers a cognitive boost. Listening to music while exercising helped to increase scores on a verbal fluency test among cardiac rehabilitation patients. "This is the first study to look at the combined effects of music and short-term exercise on mental performance," said Charles Emery, the study's lead author and a professor of psychology at "Evidence suggests that exercise improves the cognitive performance of people with coronary artery disease," Emery said. "And listening to music is thought to enhance brain power. We wanted to put the two results together." Those results appear in a recent issue of the journal Heart & Lung. The study included 33 men and women in the final weeks of a cardiac rehabilitation program. Most participants had undergone bypass surgery, angioplasty or cardiac catheterization. Coronary artery disease may compromise cognitive ability, Emery said; that's why he and his colleagues chose cardiac rehabilitation patients for this study. The researchers asked participants to complete a verbal fluency test before and after two separate sessions of exercising on a treadmill. The workouts were scheduled a week apart and lasted about 30 minutes. Participants listened to classical music – Vivaldi's "The Four Seasons" – during one of the sessions. "We used 'The Four Seasons' because of its moderate tempo and positive effects on medical patients in previous research," Emery said. "But given the range of music preferences among patients, it's especially important to evaluate the influence of other types of music on cognitive outcomes." As a way to measure anxiety and depression, participants completed a 30-item checklist before and after exercise. The list included adjectives to describe the patient's current mood. The researchers also tested each person's verbal fluency before and after each exercise session by asking participants to generate lists of words in specific categories. "This kind of task challenges the part of the brain that handles planning and abstract thought as well as a person's capacity for organized verbal processing," Emery said. Participants reported feeling better emotionally and mentally after working out regardless of whether or not they listened to music. But the improvement in verbal fluency test performance after listening to music was more than double that of the non-music condition. "Exercise seems to cause positive changes in the nervous system, and these changes may have a direct effect on cognitive ability," Emery said. "Listening to music may influence cognitive function through different pathways in the brain. The combination of music and exercise may stimulate and increase cognitive arousal while helping to organize cognitive output." Emery conducted the study with Evana Hsiao and Scott Hill, both with
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