ScienceDaily (Dec. 12, 2009) — Neurology researchers have shown that feeding amino acids to brain-injured animals restores their cognitive abilities and may set the stage for the first effective treatment for cognitive impairments suffered by people with traumatic brain injuries.
"We have shown in an animal model that dietary intervention can restore a proper balance of neurochemicals in the injured part of the brain, and simultaneously improves cognitive performance," said study leader Akiva S. Cohen, Ph.D., a neuroscientist at The Children's Hospital of Philadelphia.
The study appears December 7 in the online issue of the Proceedings of the National Academy of Sciences.
If these results in mice can be translated to human medicine, there would be a broad clinical benefit. Every 23 seconds, a man, woman or child in the United States suffers a traumatic brain injury (TBI). The primary cause of death and disability in children and young adults, TBI also accounts for permanent disabilities in more than 5 million Americans. The majority of those cases are from motor vehicle injuries, along with a rising incidence of battlefield casualties.
Although physicians can relieve the dangerous swelling that occurs after a TBI, there are currently no treatments for the underlying brain damage that brings in its wake cognitive losses in memory, learning and other functions.
The animals in the current study received a cocktail of three branched chain amino acids (BCAAs), specifically leucine, isoleucine and valine, in their drinking water. Previous researchers had shown that people with severe brain injuries showed mild functional
improvements after receiving BCAAs through an intravenous line.
BCAAs are crucial precursors of two neurotransmitters -- glutamate and gamma-aminobutyric acid, or GABA, which function together to maintain an appropriate balance of brain activity. Glutamate excites neurons, stimulating them to fire, while GABA inhibits the firing. Too much excitement or, too little, and the brain doesn't work properly. A TBI upsets the balance.
In particular, a TBI frequently damages the hippocampus, a structure deep in the brain involved in higher learning and memory. In the current study, the researchers found that an injury to the hippocampus reduced levels of BCAAs. Although overall levels of glutamate and GABA were unchanged, the loss of BCAAs disturbed the critical balance of neurotransmitters in the hippocampus, making some localized regions more excitable and others less excitable. Cohen's team tested the hypothesis that providing dietary BCAAs would restore the balance in neural response.
In this study, Cohen's study team first created standardized brain injuries in mice, and one week later compared the animals' conditioned fear response to that of uninjured mice. A week after receiving a mild electric shock in a specific cage, normal mice tend to "freeze" when placed in the same cage, anticipating another shock. The brain-injured mice demonstrated fewer freezing responses -- a sign that they had partially lost that piece of learning.
On the other hand, brain-injured mice that received a diet of BCAAs showed the same normal response as the uninjured mice. The BCAA cocktail had restored their learning ability.
In addition to the behavioral results, the team conducted electrophysiological experiments in slices of hippocampus from brain-injured and non-injured mice, and showed that BCAA restored a normal balance of neural activity. "The electrophysiological results were consistent with what we saw in the animals' functional recovery," said Cohen.
If the results in mice can be reproduced in people, patients with traumatic brain injuries could receive the BCAAs in a drink. Cohen suggests that BCAAs as a dietary supplement could have a more sustained, measured benefit than that seen when patients receive BCAAs intravenously, in which the large IV dose may flood brain receptors and have more limited benefits.
Although much work remains to be done to translate the finding into a therapy, Cohen expects to collaborate over the next year with other researchers in an early-phase clinical trial of dietary BCAAs in patients with mild to moderate TBI.
The National Institutes of Health provided funding for this study. Cohen's co-authors were Jeffrey Cole, Ph.D., Christina M. Mitala, Ph.D., Suhali Kundu and Itzhak Nissim, Ph.D., all of Children's Hospital; Jaclynn A. Elkind of the University of Pennsylvania; and Ajay Verma, M.D., Ph.D., of the Uniformed Services University of the Health Sciences, Bethesda, Md. Cohen and Nissim are also on the faculty of the University of Pennsylvania School of Medicine.
Monday, December 14, 2009
Wednesday, October 21, 2009
Researchers Optimizing Progesterone For Brain Injury Treatment
ScienceDaily (Oct. 21, 2009) — As doctors begin to test progesterone for traumatic brain injury at sites across the country, researchers are looking ahead to optimizing the hormone's effectiveness.
Two abstracts summarizing Emory research on progesterone are being presented at the 2009 Society for Neuroscience (SFN) meeting in Chicago.
A multisite phase III clinical trial called ProTECT III will begin to evaluate progesterone's effectiveness for treating traumatic brain injury early next year. The trial grows out of years of research by Donald Stein, PhD, Asa G. Candler Professor of Emergency Medicine at Emory School of Medicine, demonstrating that progesterone can protect damaged brain tissue. Stein is director of the Department of Emergency Medicine's Brain Research Laboratory.
One of the SFN abstracts reports on progesterone analogues that are more water-soluble. This work comes from Stein and his colleagues in collaboration with the laboratory of Dennis Liotta, PhD, Emory professor of chemistry.
Currently, the lack of water solubility limits delivery of progesterone, in that the hormone must be prepared hours ahead and cannot be kept at room temperature. Small chemical modifications may allow similar compounds with the same effects as progesterone to be given to patients closer to the time of injury.
According to the results, two compounds similar to progesterone showed an equivalent ability to reduce brain swelling in an animal model of traumatic brain injury.
The second abstract describes evidence that adding vitamin D to progesterone enhances the hormone's effectiveness when applied to neurons under stress in the laboratory. Like progesterone, vitamin D is a steroid hormone that is inexpensive, has good safety properties and acts on many different biochemical pathways.
The authors showed that a low amount of vitamin D boosted the ability of progesterone to protect neurons from excito-toxicity , a principal cause of brain injury and cell death.
Two abstracts summarizing Emory research on progesterone are being presented at the 2009 Society for Neuroscience (SFN) meeting in Chicago.
A multisite phase III clinical trial called ProTECT III will begin to evaluate progesterone's effectiveness for treating traumatic brain injury early next year. The trial grows out of years of research by Donald Stein, PhD, Asa G. Candler Professor of Emergency Medicine at Emory School of Medicine, demonstrating that progesterone can protect damaged brain tissue. Stein is director of the Department of Emergency Medicine's Brain Research Laboratory.
One of the SFN abstracts reports on progesterone analogues that are more water-soluble. This work comes from Stein and his colleagues in collaboration with the laboratory of Dennis Liotta, PhD, Emory professor of chemistry.
Currently, the lack of water solubility limits delivery of progesterone, in that the hormone must be prepared hours ahead and cannot be kept at room temperature. Small chemical modifications may allow similar compounds with the same effects as progesterone to be given to patients closer to the time of injury.
According to the results, two compounds similar to progesterone showed an equivalent ability to reduce brain swelling in an animal model of traumatic brain injury.
The second abstract describes evidence that adding vitamin D to progesterone enhances the hormone's effectiveness when applied to neurons under stress in the laboratory. Like progesterone, vitamin D is a steroid hormone that is inexpensive, has good safety properties and acts on many different biochemical pathways.
The authors showed that a low amount of vitamin D boosted the ability of progesterone to protect neurons from excito-toxicity , a principal cause of brain injury and cell death.
Monday, October 12, 2009
Key Mechanism In Brain Development Pinpointed, Raising Questions About Use Of Antiseizure Drugs
ScienceDaily (Oct. 12, 2009) — Researchers at the Stanford University School of Medicine have identified a key molecular player in guiding the formation of synapses — the all-important connections between nerve cells — in the brain. This discovery, based on experiments in cell culture and in mice, could advance scientists' understanding of how young children's brains develop as well as point to new approaches toward countering brain disorders in adults.
The new work also pinpoints, for the first time, the biochemical mechanism by which the widely prescribed drug gabapentin (also marketed under the trade name Neurontin) works. "We have solved the longstanding mystery of how this blockbuster drug acts," said Ben Barres, MD, PhD, professor and chair of neurobiology.
The study shows that gabapentin halts the formation of new synapses, possibly explaining its therapeutic value in mitigating epileptic seizures and chronic pain. This insight, however, may lead physicians to reconsider the circumstances in which the drug should be prescribed to pregnant women.
The paper, to be published online Oct. 8 in the journal Cell, looks at the interaction between neurons — the extensively researched nerve cells that account for 10 percent of the cells in the brain — and the less-studied but much more common brain cells called astrocytes. Much work has been done on how neurons transmit electrical signals to each other through synapses — the nanoscale electrochemical contact points between neurons. It is the brain's circuitry of some 100 trillion of these synapses that allow us to think, feel, remember and move.
It is commonly agreed that the precise placement and strength of each person's trillions of synaptic connections closely maps with that person's cognitive, emotional and behavioral makeup. But exactly why a particular synapse is formed in a certain place at a certain time has largely remained a mystery.
In 2005, Barres took a big step toward explaining this process when he and his colleagues discovered that a protein astrocytes secrete, called thrombospondin, is essential to the formation of this complex brain circuitry. Still, no one knew the precise mechanism by which thrombospondin induced synapse formation.
In this new study, Barres, lead author Cagla Eroglu, PhD, and their colleagues demonstrate how thrombospondin binds to a receptor found on neurons' outer membranes. The role of this receptor, known as alpha2delta-1, had been obscure until now. But in an experiment with mice, the scientists found that neurons lacking alpha2delta-1 were unable to form synapses in response to thrombospondin stimulation.
And when the researchers grew neurons in a dish that were bioengineered to overexpress this receptor, those neurons produced twice as many synapses in response to stimulation with thrombospondin than did their ummodified counterparts.
The new discovery about alpha2delta-1's key role in synapse formation carries important implications for understanding the cause of pain and of epilepsy and developing improved medications for these conditions.
It was already known that alpha2delta-1 is the neuronal receptor for gabapentin, one of the world's most widely administered medications.
Gabapentin is often prescribed for epilepsy and chronic pain, and its off-label use for other indications is widespread. Up to now, the molecular mechanism of gabapentin's action — what, exactly, it's doing to counter seizures or chronic pain — was unknown. But both syndromes may involve excessive numbers of synaptic connections in local areas of the brain.
In their new study, Barres and his colleagues found that when gabapentin was administered in developing mice, it bound to alpha2delta-1, preventing thrombospondin from binding to the receptor and, in turn, impeding synapse formation. Likewise, by blocking thrombosponin, gabapentin may reduce excess synapse formation in vulnerable areas of the human brain.
Barres noted that he and his colleagues found that gabapentin does not dissolve pre-existing synapses, but only prevents formation of new ones. That greatly diminishes gabapentin's potential danger to adults. In mature human brains, astrocytes ordinarily produce very little thrombospondin, and adult neurons don't form many new synapses, although some new synapses do continue to be formed throughout life — for example, in a part of the brain where new memories are laid down and at sites of injury to neurons, such as occurs after a stroke.
But the new findings raise questions about gabapentin's effect in situations where synapse formation is widespread and crucial, most notably in pregnancies. The vast bulk of the brain's synapses are formed during gestation and the very early months and years after birth. Because gabapentin easily crosses the placental barrier, it could potentially interfere with a fetus' rapidly developing brain just when global synapse formation is proceeding at breakneck speed.
"It's a bit scary that a drug that can so powerfully block synapse formation is being used in pregnant women," Barres said. "This potential effect on fetal brains needs to be taken seriously. Right now, doctors have the view that gabapentin is the safest anticonvulsant. There is no question that pregnant women with epilepsy who have been advised by their neurologists to continue their anticonvulsant treatment with gabapentin during their pregnancy should definitely remain on this drug until instructed otherwise. But there is no long-term registry being kept to track gabapentin-exposed babies. Our findings are saying that we need to be following up on these newborns so that their cognitive performance can be studied as they grow older."
Eroglu, then a postdoctoral researcher in Barres' laboratory, is now an assistant professor of cell biology at Duke University in Durham, N.C. Other Stanford co-authors were Nicola Allen, PhD; Michael Susman; Nancy O'Rourke, PhD; Chan Young Park, PhD; Engin Ozkan, PhD; Chandrani Chakraborty; Sara Mulinyawe; Andrew Huberman; PhD; Eric Green, MD, PhD; Ricardo Dolmetsch, PhD; Christopher Garcia, PhD; and Stephen Smith, PhD. Funding was provided by the National Institute of Drug Addiction; the National Heart, Lung and Blood Institute; the National Institutes of Health; the Human Frontiers Scientific Program and a Helen Hay Whitney postdoctoral fellowship.
The new work also pinpoints, for the first time, the biochemical mechanism by which the widely prescribed drug gabapentin (also marketed under the trade name Neurontin) works. "We have solved the longstanding mystery of how this blockbuster drug acts," said Ben Barres, MD, PhD, professor and chair of neurobiology.
The study shows that gabapentin halts the formation of new synapses, possibly explaining its therapeutic value in mitigating epileptic seizures and chronic pain. This insight, however, may lead physicians to reconsider the circumstances in which the drug should be prescribed to pregnant women.
The paper, to be published online Oct. 8 in the journal Cell, looks at the interaction between neurons — the extensively researched nerve cells that account for 10 percent of the cells in the brain — and the less-studied but much more common brain cells called astrocytes. Much work has been done on how neurons transmit electrical signals to each other through synapses — the nanoscale electrochemical contact points between neurons. It is the brain's circuitry of some 100 trillion of these synapses that allow us to think, feel, remember and move.
It is commonly agreed that the precise placement and strength of each person's trillions of synaptic connections closely maps with that person's cognitive, emotional and behavioral makeup. But exactly why a particular synapse is formed in a certain place at a certain time has largely remained a mystery.
In 2005, Barres took a big step toward explaining this process when he and his colleagues discovered that a protein astrocytes secrete, called thrombospondin, is essential to the formation of this complex brain circuitry. Still, no one knew the precise mechanism by which thrombospondin induced synapse formation.
In this new study, Barres, lead author Cagla Eroglu, PhD, and their colleagues demonstrate how thrombospondin binds to a receptor found on neurons' outer membranes. The role of this receptor, known as alpha2delta-1, had been obscure until now. But in an experiment with mice, the scientists found that neurons lacking alpha2delta-1 were unable to form synapses in response to thrombospondin stimulation.
And when the researchers grew neurons in a dish that were bioengineered to overexpress this receptor, those neurons produced twice as many synapses in response to stimulation with thrombospondin than did their ummodified counterparts.
The new discovery about alpha2delta-1's key role in synapse formation carries important implications for understanding the cause of pain and of epilepsy and developing improved medications for these conditions.
It was already known that alpha2delta-1 is the neuronal receptor for gabapentin, one of the world's most widely administered medications.
Gabapentin is often prescribed for epilepsy and chronic pain, and its off-label use for other indications is widespread. Up to now, the molecular mechanism of gabapentin's action — what, exactly, it's doing to counter seizures or chronic pain — was unknown. But both syndromes may involve excessive numbers of synaptic connections in local areas of the brain.
In their new study, Barres and his colleagues found that when gabapentin was administered in developing mice, it bound to alpha2delta-1, preventing thrombospondin from binding to the receptor and, in turn, impeding synapse formation. Likewise, by blocking thrombosponin, gabapentin may reduce excess synapse formation in vulnerable areas of the human brain.
Barres noted that he and his colleagues found that gabapentin does not dissolve pre-existing synapses, but only prevents formation of new ones. That greatly diminishes gabapentin's potential danger to adults. In mature human brains, astrocytes ordinarily produce very little thrombospondin, and adult neurons don't form many new synapses, although some new synapses do continue to be formed throughout life — for example, in a part of the brain where new memories are laid down and at sites of injury to neurons, such as occurs after a stroke.
But the new findings raise questions about gabapentin's effect in situations where synapse formation is widespread and crucial, most notably in pregnancies. The vast bulk of the brain's synapses are formed during gestation and the very early months and years after birth. Because gabapentin easily crosses the placental barrier, it could potentially interfere with a fetus' rapidly developing brain just when global synapse formation is proceeding at breakneck speed.
"It's a bit scary that a drug that can so powerfully block synapse formation is being used in pregnant women," Barres said. "This potential effect on fetal brains needs to be taken seriously. Right now, doctors have the view that gabapentin is the safest anticonvulsant. There is no question that pregnant women with epilepsy who have been advised by their neurologists to continue their anticonvulsant treatment with gabapentin during their pregnancy should definitely remain on this drug until instructed otherwise. But there is no long-term registry being kept to track gabapentin-exposed babies. Our findings are saying that we need to be following up on these newborns so that their cognitive performance can be studied as they grow older."
Eroglu, then a postdoctoral researcher in Barres' laboratory, is now an assistant professor of cell biology at Duke University in Durham, N.C. Other Stanford co-authors were Nicola Allen, PhD; Michael Susman; Nancy O'Rourke, PhD; Chan Young Park, PhD; Engin Ozkan, PhD; Chandrani Chakraborty; Sara Mulinyawe; Andrew Huberman; PhD; Eric Green, MD, PhD; Ricardo Dolmetsch, PhD; Christopher Garcia, PhD; and Stephen Smith, PhD. Funding was provided by the National Institute of Drug Addiction; the National Heart, Lung and Blood Institute; the National Institutes of Health; the Human Frontiers Scientific Program and a Helen Hay Whitney postdoctoral fellowship.
Saturday, August 15, 2009
Brain Damage Seen On Brain Scans May Predict Memory Loss In Old Age
ScienceDaily (Aug. 14, 2009) — Areas of brain damage seen on brain scans and originally thought to be related to stroke may help doctors predict a person's risk of memory problems in old age, according to research published in the August 11, 2009, print issue of Neurology®, the medical journal of the American Academy of Neurology.
Researchers tested 679 people age 65 and older without dementia for mild cognitive impairment, the stage between normal aging and dementia. Participants underwent brain scans where scientists looked for small areas of brain damage called white matter hyperintensities, often referred to as ministrokes. They also looked for infarcts, or areas of dead tissue usually called strokes. Both types of brain damage may be caused by vascular disease in the brain.
The study found that people with white matter hyperintensities were nearly twice as likely to have mild cognitive impairment that included memory loss. However, people who had infarcts on their brain scans were more likely to experience mild cognitive impairment in abilities other than memory loss.
The results remained the same regardless of a person's age, gender, ethnic group, education, and if they had a gene thought to be a strong risk factor for dementia, called the ApoEe4 gene.
"The most interesting finding in this study was that white matter hyperintensities, or ministrokes, predicted memory problems, while strokes predicted non-memory problems," said study author José Luchsinger, MD, MPH, with Columbia University Medical Center in New York.
"Traditionally, ministrokes and strokes are thought to have a common origin and to more strongly predict non-memory cognitive problems. There are an increasing number of studies challenging the idea that all white matter hyperintensities are similar to strokes. The fact that white matter hyperintensities more strongly predicted memory problems could challenge traditional views that white matter hyperintensities are milder versions of stroke that are produced only by conditions such as high blood pressure," said Luchsinger.
Luchsinger says more work is needed to understand white matter hyperintensities and to identify which are related to stroke and which are related to other conditions such as Alzheimer's disease. He says this could eventually help doctors and researchers to design preventive strategies for memory and other types of cognitive impairment.
The study was supported by the National Institutes of Health.
Researchers tested 679 people age 65 and older without dementia for mild cognitive impairment, the stage between normal aging and dementia. Participants underwent brain scans where scientists looked for small areas of brain damage called white matter hyperintensities, often referred to as ministrokes. They also looked for infarcts, or areas of dead tissue usually called strokes. Both types of brain damage may be caused by vascular disease in the brain.
The study found that people with white matter hyperintensities were nearly twice as likely to have mild cognitive impairment that included memory loss. However, people who had infarcts on their brain scans were more likely to experience mild cognitive impairment in abilities other than memory loss.
The results remained the same regardless of a person's age, gender, ethnic group, education, and if they had a gene thought to be a strong risk factor for dementia, called the ApoEe4 gene.
"The most interesting finding in this study was that white matter hyperintensities, or ministrokes, predicted memory problems, while strokes predicted non-memory problems," said study author José Luchsinger, MD, MPH, with Columbia University Medical Center in New York.
"Traditionally, ministrokes and strokes are thought to have a common origin and to more strongly predict non-memory cognitive problems. There are an increasing number of studies challenging the idea that all white matter hyperintensities are similar to strokes. The fact that white matter hyperintensities more strongly predicted memory problems could challenge traditional views that white matter hyperintensities are milder versions of stroke that are produced only by conditions such as high blood pressure," said Luchsinger.
Luchsinger says more work is needed to understand white matter hyperintensities and to identify which are related to stroke and which are related to other conditions such as Alzheimer's disease. He says this could eventually help doctors and researchers to design preventive strategies for memory and other types of cognitive impairment.
The study was supported by the National Institutes of Health.
Reduction of Alzheimer's Disease and Lifestyle Changes
People may be able to reduce their risk of developing Alzheimer's disease, according to two recently published studies that are the latest in a long line of research. But does that hold for everyone? And by how much can you lower the risk? Here's a look at the facts. Alzheimer's afflicts 5.3 million Americans and that number is predicted to grow to nearly 8 million in the next 20 years, according to a 2009 report by the Alzheimer's Assn. Because the disease has no cure, medical researchers continue to focus on preventing or delaying the disease.
Two weeks ago, a paper in the journal Dementia and Geriatric Cognitive Disorders reported that people with even moderately elevated cholesterol in their 40s have twice the risk of developing Alzheimer's disease in their 60s, 70s and 80s, adding blood cholesterol to a variety of already-known risk factors for the disorder. High blood pressure, diabetes, obesity, smoking and high-fat diets have all been associated with increasing one's risk. Last week, a paper in the Journal of the American Medical Assn. reported that people eating a so-called Mediterranean diet and exercising regularly were at lower risk -- by as much as 50%. And in earlier studies, other lifestyle factors -- such as doing the daily crossword puzzle or other intellectually stimulating activities, maintaining an active social life and getting a college education -- have been associated with lowered Alzheimer's risk. The recent cholesterol study was large and long -- 9,844 Californians were followed for three decades -- and the data are striking. People with high cholesterol -- 240 or higher -- were 57% more likely to develop Alzheimer's disease. Those with borderline range cholesterol -- 200 to 239 -- were 23% more likely. Still, this is an association at best. No one can say that high cholesterol causes Alzheimer's disease: Other factors linked to it in some way could be to blame. Also not known is whether lowering cholesterol -- for instance by taking statin drugs -- would be protective. "An association is hypothesis-generating -- it allows us to begin looking at why that relationship might exist," says Dr. Jeffrey Cummings, director of the Mary S. Easton Center for Alzheimer's Disease Research at UCLA. One possible clue comes from animal studies: Neurobiological studies have found that high cholesterol in the blood may trigger more of the brain-clogging substance beta-amyloid protein.
The diet and exercise study reported last week was smaller and shorter. In it, 1,880 elderly New Yorkers were followed for an average of 5 1/2 years. It found exercise alone was linked to as much as a 50% reduced risk, diet alone by as much as 40%. This is not the first study to suggest that diet and physical activity may be protective. The Mediterranean-type diet "combines several foods and nutrients potentially protective against cognitive dysfunction or dementia, such as fish, monounsaturated fatty acids, vitamins B12 and folate, antioxidants (vitamin E, carotenoids, flavonoids), and moderate amounts of alcohol," the authors wrote. There have been very few studies that meet the gold standard of human trials, in which people would be randomly assigned to either receive an intervention or not, then followed into their senior years to see if they develop Alzheimer's. Of trials that have been completed, no clear preventive treatment has been identified.Some studies have found that in patients with hypertension, blood-pressure-lowering medications reduced the risk of Alzheimer's disease; others have found no effect. The same is true for cholesterol-lowering medications and diabetes management -- some studies found lower risk for Alzheimer's and others found no difference. Similarly, several clinical trials that have tested cholesterol-lowering statin drugs in elderly patients have failed to find lowered risk. But "it doesn't invalidate the cholesterol story," Cummings says. "What it does is suggest that by the time you get to the end of this lifelong process, it's too late to do a meaningful intervention. Increasingly, we see Alzheimer's disease as a result of a lifelong process as opposed to simply a late-onset brain disease." Scientists generally agree that keeping cardiovascular risk factors in check is good for the brain as well as the heart. "The damage that those factors cause on the vessels of the heart, for instance, are exactly the same kind of damage that's caused in the brain," says Lenore Launer, chief of neuroepidemiology at the National Institute on Aging in Bethesda, Md. "The vasculature is impaired in some way and then the neurons may die."But that is just part of the story. Certain naturally occurring neuroprotective substances are stimulated by physical activity, Cummings says. "So there are direct neurobiological effects of exercise that go beyond just better blood flow." These effects of lifestyle on Alzheimer's are not yet proven. But -- in contrast to long-term drug treatments -- there is virtually no downside to recommending them, experts say. Cummings says he often fields questions from families of his patients about what they can do to prevent the disease from happening to them. He recommends supplements of vitamins C and E and omega-3 fatty acids, exercise three times per week for 30 minutes and taking care of one's cardiovascular risk factors such as blood pressure and cholesterol. Even in people with genetic predisposition for developing Alzheimer's (those who carry the apolipoprotein E-e4 gene have a doubled risk), lifestyle changes can make a difference, Cummings says. "My experience is that people who know that they're at genetic risk take the environmental interventions much more seriously." Debra Cherry, executive vice president of the Alzheimer's Assn. California Southland Chapter, says that when she served on the Healthy Brain Initiative, a government workshop seeking evidence-based recommendations for reducing risk, the strongest case made was for aerobic activity. "I don't know if anyone will ever be able to do a randomized, controlled study, but the evidence is pretty strong that aerobic exercise protects again heart disease and brain disease," she says. "And there's very little risk to doing it
Two weeks ago, a paper in the journal Dementia and Geriatric Cognitive Disorders reported that people with even moderately elevated cholesterol in their 40s have twice the risk of developing Alzheimer's disease in their 60s, 70s and 80s, adding blood cholesterol to a variety of already-known risk factors for the disorder. High blood pressure, diabetes, obesity, smoking and high-fat diets have all been associated with increasing one's risk. Last week, a paper in the Journal of the American Medical Assn. reported that people eating a so-called Mediterranean diet and exercising regularly were at lower risk -- by as much as 50%. And in earlier studies, other lifestyle factors -- such as doing the daily crossword puzzle or other intellectually stimulating activities, maintaining an active social life and getting a college education -- have been associated with lowered Alzheimer's risk. The recent cholesterol study was large and long -- 9,844 Californians were followed for three decades -- and the data are striking. People with high cholesterol -- 240 or higher -- were 57% more likely to develop Alzheimer's disease. Those with borderline range cholesterol -- 200 to 239 -- were 23% more likely. Still, this is an association at best. No one can say that high cholesterol causes Alzheimer's disease: Other factors linked to it in some way could be to blame. Also not known is whether lowering cholesterol -- for instance by taking statin drugs -- would be protective. "An association is hypothesis-generating -- it allows us to begin looking at why that relationship might exist," says Dr. Jeffrey Cummings, director of the Mary S. Easton Center for Alzheimer's Disease Research at UCLA. One possible clue comes from animal studies: Neurobiological studies have found that high cholesterol in the blood may trigger more of the brain-clogging substance beta-amyloid protein.
The diet and exercise study reported last week was smaller and shorter. In it, 1,880 elderly New Yorkers were followed for an average of 5 1/2 years. It found exercise alone was linked to as much as a 50% reduced risk, diet alone by as much as 40%. This is not the first study to suggest that diet and physical activity may be protective. The Mediterranean-type diet "combines several foods and nutrients potentially protective against cognitive dysfunction or dementia, such as fish, monounsaturated fatty acids, vitamins B12 and folate, antioxidants (vitamin E, carotenoids, flavonoids), and moderate amounts of alcohol," the authors wrote. There have been very few studies that meet the gold standard of human trials, in which people would be randomly assigned to either receive an intervention or not, then followed into their senior years to see if they develop Alzheimer's. Of trials that have been completed, no clear preventive treatment has been identified.Some studies have found that in patients with hypertension, blood-pressure-lowering medications reduced the risk of Alzheimer's disease; others have found no effect. The same is true for cholesterol-lowering medications and diabetes management -- some studies found lower risk for Alzheimer's and others found no difference. Similarly, several clinical trials that have tested cholesterol-lowering statin drugs in elderly patients have failed to find lowered risk. But "it doesn't invalidate the cholesterol story," Cummings says. "What it does is suggest that by the time you get to the end of this lifelong process, it's too late to do a meaningful intervention. Increasingly, we see Alzheimer's disease as a result of a lifelong process as opposed to simply a late-onset brain disease." Scientists generally agree that keeping cardiovascular risk factors in check is good for the brain as well as the heart. "The damage that those factors cause on the vessels of the heart, for instance, are exactly the same kind of damage that's caused in the brain," says Lenore Launer, chief of neuroepidemiology at the National Institute on Aging in Bethesda, Md. "The vasculature is impaired in some way and then the neurons may die."But that is just part of the story. Certain naturally occurring neuroprotective substances are stimulated by physical activity, Cummings says. "So there are direct neurobiological effects of exercise that go beyond just better blood flow." These effects of lifestyle on Alzheimer's are not yet proven. But -- in contrast to long-term drug treatments -- there is virtually no downside to recommending them, experts say. Cummings says he often fields questions from families of his patients about what they can do to prevent the disease from happening to them. He recommends supplements of vitamins C and E and omega-3 fatty acids, exercise three times per week for 30 minutes and taking care of one's cardiovascular risk factors such as blood pressure and cholesterol. Even in people with genetic predisposition for developing Alzheimer's (those who carry the apolipoprotein E-e4 gene have a doubled risk), lifestyle changes can make a difference, Cummings says. "My experience is that people who know that they're at genetic risk take the environmental interventions much more seriously." Debra Cherry, executive vice president of the Alzheimer's Assn. California Southland Chapter, says that when she served on the Healthy Brain Initiative, a government workshop seeking evidence-based recommendations for reducing risk, the strongest case made was for aerobic activity. "I don't know if anyone will ever be able to do a randomized, controlled study, but the evidence is pretty strong that aerobic exercise protects again heart disease and brain disease," she says. "And there's very little risk to doing it
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