ScienceDaily (Dec. 12, 2009) — We have all had the embarrassing experience of seeing an acquaintance in an unfamiliar setting. We know we know them but can't recall who they are. But with the correct cues from conversation or context, something seems to click and we can readily access very rich and vivid memories about the individual.
A team of researchers from the University of Toronto and the Krembil Neuroscience Centre at the University Health Network have shed some light on this mysterious process, discovering that the hippocampus, a brain region in the temporal lobe, is only involved when cues enable us to recall these rich memories.
"We used a technique called functional Magnetic Resonance Imaging (fMRI) that allows us to identify brain regions engaged during specific types of mental processes," says Melanie Cohn, a postdoctoral fellow in neuropsychology and lead author of the paper published online December 8 by the Proceedings of the National Academy of Sciences.
In the first stage of the study, healthy young adults were exposed to pairings of oddly unrelated words, such as "alligator" and "chair," and invited to learn them by putting them in the same sentence and so on. Next, while being scanned in the fMRI, participants were shown a series of single words -- some of which had been studied in the word pairings and some of which had not. Participants were asked to rate their memory for each word in terms of how confident they were that it was a word that they had studied earlier or not.
After each decision, participants were given a cue: the word was presented along with the word it was initially paired with. For about half of the familiar words, ie those that subjects recalled learning earlier, the pairing triggered rich detailed memories of the context -- such as the sentence they had made up to include both words -- in which the original pairing was learned. The fMRI scan showed hippocampus activity only when cues were used to retrieve memories.
"This study is important because it resolves a current debate on the role of the hippocampus in retrieving memories.
Some have argued it is the strength of the memory that matters most in retrieval. We have shown it is actually context that activates the hippocampus," explains Cohn. The findings also have direct relevance to understanding the type of memory problems found in Epilepsy or Alzheimer's, diseases in which patients have suffered damage to the hippocampus "Being able to characterize specific types of memory loss will lead to development of better clinical measures for diagnosis and monitoring of temporal-lobe dysfunction," she says
Other research team members from the University of Toronto's Department of Psychology are Mary Pat McAndrews, who also holds an appointment with the Krembil Neuroscience Centre, Ayelet Lahat and Morris Moscovitch. Programming and data analysis were done by Marilyne Ziegler, Sybille Schulz, Megan Walberg and Deborah Shwartz, all members of the University of Toronto's Department of Psychology. Research was funded by the Canadian Institutes of Health Research.
Monday, December 14, 2009
With Amino Acid, Mice Improve Memory After Brain Injury
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.
"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.
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
Friday, July 24, 2009
Post-Traumatic-Stress-Disorder Associated With HIgher ALzheimer's Dementia Risk
ScienceDaily (July 24, 2009) — Though discoveries about Alzheimer's disease risk factors are often in the news, adults do not know about the relationship between Alzheimer's disease risk and heart health, nor that physical activity can be protective against dementia, according to new research reported at the Alzheimer's Association 2009 International Conference on Alzheimer's Disease (ICAD 2009) in Vienna.
An additional study reported at ICAD 2009 shows higher Alzheimer's risk in veterans with post-traumatic stress disorder (PTSD).
"Your brain plays a critical role in almost everything you do: thinking, feeling, remembering, working, and playing – even sleeping," said Maria Carrillo, PhD, Director of Medical & Scientific Relations at the Alzheimer's Association. "The good news is that we now know there's a lot you can do to help keep your brain healthier as you age. These steps might also reduce your risk of developing Alzheimer's disease or another dementia."
"There's a strong and credible association between heart health and brain health. If people learn about and do some simple lifestyle modifications, such as being more physically active and eating a brain healthy diet, it could have an enormous impact on our nation's public health and the cost of healthcare," Carrillo added.
Adults Show a Poor Understanding of Alzheimer's Link to Heart Health Risk Factors
Colleen E. Jackson, M.S., a doctoral student in Clinical Psychology at the University of Connecticut, and colleagues conducted an anonymous online survey of 690 adults to measure "dementia literacy," that is, their knowledge and beliefs that may assist in the recognition, management, or prevention of Alzheimer's.
Mean age of the population was 50 years, the range was 30-85 years; 76% of respondents were female. Ninety-four percent (94%) of participants were from the United States, with the remaining 6% from other English-speaking countries. The sample was relatively wealthy, with 18% of respondents making more than $200,000 per year at the peak of their careers, and well-educated, with 87% of respondents having completed at least 1-3 years of college.
The researchers found that 64% of study participants incorrectly indicated no association between Alzheimer's and obesity or high blood pressure. Sixty-six percent (66%) did not know that high stress is a risk factor for dementia, and 34% did not know that physical exercise is a protective factor.
On the positive side, nearly all study participants (94%) correctly indicated that Alzheimer's is not normal aging, and is not completely based on genetics.
"Our data suggest that American adults have limited knowledge and a poor understanding of factors that have been demonstrated to increase risk for Alzheimer's, such as obesity, high blood pressure, and other heart health risk factors," Jackson said. "They also didn't know much about protective factors against Alzheimer's, such as physical exercise, relative to the strength of the available research evidence."
"We need more education programs and opportunities, across all demographic groups, focusing on behaviors that modify your risk for developing Alzheimer's disease," Jackson added.
PTSD Linked to Nearly Double Dementia Risk in Veterans
Post-traumatic stress disorder (PTSD) is common among veterans returning from combat and there is some evidence that it may be associated with reduced cognitive function. However, no study has yet investigated if PTSD increases the risk of developing dementia.
To address this emerging issue, Kristine Yaffe, MD, Professor of Psychiatry, Neurology and Epidemiology and Associate Chair of Research for the Department of Psychiatry at the University of California, San Francisco, and Chief of Geriatric Psychiatry and Director of the Memory Disorders Clinic at the San Francisco VA Medical Center, and colleagues sought to determine if PTSD is associated with risk of developing dementia among older veterans in the U.S. receiving treatment in veterans' medical centers.
They studied 181,093 veterans aged 55 years and older without dementia (53,155 veterans diagnosed with PTSD and 127,938 veterans without PTSD) using data from the Department of Veterans Affairs National Patient Care Database. Mean baseline age of the veterans was 68.8 years and 97% were male. They followed the veterans from 2001 through 2007, including tracking whether they were diagnosed with Alzheimer's/dementia.
The researchers found that veterans with PTSD in the study developed new cases of dementia at a rate of 10.6% over the seven years of follow-up; those without PTSD had a rate of 6.6%. (Note: This is updated data from the researcher, which is why it differs from the attached abstract.) Even after adjusting for demographics, and medical and psychiatric comorbidities, PTSD patients in this study were still nearly twice as likely to develop incident dementia compared to veterans without PTSD (HR = 1.8, 95% CI 1.7-1.9). Results were similar when they excluded those with a history of traumatic brain injury, substance abuse or depression.
"It is critical to follow patients with PTSD, and evaluate them early for dementia," Yaffe said. "Further research is needed to fully understand what links these two important disorders. With that knowledge we may be able to find ways to reduce the increased risk of dementia associated with PTSD."
An additional study reported at ICAD 2009 shows higher Alzheimer's risk in veterans with post-traumatic stress disorder (PTSD).
"Your brain plays a critical role in almost everything you do: thinking, feeling, remembering, working, and playing – even sleeping," said Maria Carrillo, PhD, Director of Medical & Scientific Relations at the Alzheimer's Association. "The good news is that we now know there's a lot you can do to help keep your brain healthier as you age. These steps might also reduce your risk of developing Alzheimer's disease or another dementia."
"There's a strong and credible association between heart health and brain health. If people learn about and do some simple lifestyle modifications, such as being more physically active and eating a brain healthy diet, it could have an enormous impact on our nation's public health and the cost of healthcare," Carrillo added.
Adults Show a Poor Understanding of Alzheimer's Link to Heart Health Risk Factors
Colleen E. Jackson, M.S., a doctoral student in Clinical Psychology at the University of Connecticut, and colleagues conducted an anonymous online survey of 690 adults to measure "dementia literacy," that is, their knowledge and beliefs that may assist in the recognition, management, or prevention of Alzheimer's.
Mean age of the population was 50 years, the range was 30-85 years; 76% of respondents were female. Ninety-four percent (94%) of participants were from the United States, with the remaining 6% from other English-speaking countries. The sample was relatively wealthy, with 18% of respondents making more than $200,000 per year at the peak of their careers, and well-educated, with 87% of respondents having completed at least 1-3 years of college.
The researchers found that 64% of study participants incorrectly indicated no association between Alzheimer's and obesity or high blood pressure. Sixty-six percent (66%) did not know that high stress is a risk factor for dementia, and 34% did not know that physical exercise is a protective factor.
On the positive side, nearly all study participants (94%) correctly indicated that Alzheimer's is not normal aging, and is not completely based on genetics.
"Our data suggest that American adults have limited knowledge and a poor understanding of factors that have been demonstrated to increase risk for Alzheimer's, such as obesity, high blood pressure, and other heart health risk factors," Jackson said. "They also didn't know much about protective factors against Alzheimer's, such as physical exercise, relative to the strength of the available research evidence."
"We need more education programs and opportunities, across all demographic groups, focusing on behaviors that modify your risk for developing Alzheimer's disease," Jackson added.
PTSD Linked to Nearly Double Dementia Risk in Veterans
Post-traumatic stress disorder (PTSD) is common among veterans returning from combat and there is some evidence that it may be associated with reduced cognitive function. However, no study has yet investigated if PTSD increases the risk of developing dementia.
To address this emerging issue, Kristine Yaffe, MD, Professor of Psychiatry, Neurology and Epidemiology and Associate Chair of Research for the Department of Psychiatry at the University of California, San Francisco, and Chief of Geriatric Psychiatry and Director of the Memory Disorders Clinic at the San Francisco VA Medical Center, and colleagues sought to determine if PTSD is associated with risk of developing dementia among older veterans in the U.S. receiving treatment in veterans' medical centers.
They studied 181,093 veterans aged 55 years and older without dementia (53,155 veterans diagnosed with PTSD and 127,938 veterans without PTSD) using data from the Department of Veterans Affairs National Patient Care Database. Mean baseline age of the veterans was 68.8 years and 97% were male. They followed the veterans from 2001 through 2007, including tracking whether they were diagnosed with Alzheimer's/dementia.
The researchers found that veterans with PTSD in the study developed new cases of dementia at a rate of 10.6% over the seven years of follow-up; those without PTSD had a rate of 6.6%. (Note: This is updated data from the researcher, which is why it differs from the attached abstract.) Even after adjusting for demographics, and medical and psychiatric comorbidities, PTSD patients in this study were still nearly twice as likely to develop incident dementia compared to veterans without PTSD (HR = 1.8, 95% CI 1.7-1.9). Results were similar when they excluded those with a history of traumatic brain injury, substance abuse or depression.
"It is critical to follow patients with PTSD, and evaluate them early for dementia," Yaffe said. "Further research is needed to fully understand what links these two important disorders. With that knowledge we may be able to find ways to reduce the increased risk of dementia associated with PTSD."
Monday, June 22, 2009
First Image of Memories Being Made
ScienceDaily (June 19, 2009) — The ability to learn and to establish new memories is essential to our daily existence and identity; enabling us to navigate through the world. A new study by researchers at the Montreal Neurological Institute and Hospital (The Neuro), McGill University and University of California, Los Angeles has captured an image for the first time of a mechanism, specifically protein translation, which underlies long-term memory formation.
The finding provides the first visual evidence that when a new memory is formed new proteins are made locally at the synapse - the connection between nerve cells - increasing the strength of the synaptic connection and reinforcing the memory. The study published in Science, is important for understanding how memory traces are created and the ability to monitor it in real time will allow a detailed understanding of how memories are formed.
When considering what might be going on in the brain at a molecular level two essential properties of memory need to be taken into account. First, because a lot of information needs to be maintained over a long time there has to be some degree of stability. Second, to allow for learning and adaptation the system also needs to be highly flexible. For this reason, research has focused on synapses which are the main site of exchange and storage in the brain. They form a vast but also constantly fluctuating network of connections whose ability to change and adapt, called synaptic plasticity, may be the fundamental basis of learning and memory. "But, if this network is constantly changing, the question is how do memories stay put, how are they formed? It has been known for some time that an important step in long-term memory formation is "translation", or the production, of new proteins locally at the synapse, strengthening the synaptic connection in the reinforcement of a memory, which until now has never been imaged," says Dr. Wayne Sossin, neuroscientist at The Neuro and co-investigator in the study. "Using a translational reporter, a fluorescent protein that can be easily detected and tracked, we directly visualized the increased local translation, or protein synthesis, during memory formation. Importantly, this translation was synapse-specific and it required activation of the post-synaptic cell, showing that this step required cooperation between the pre and post-synaptic compartments, the parts of the two neurons that meet at the synapse. Thus highly regulated local translation occurs at synapses during long-term plasticity and requires trans-synaptic signals."
Long-term memory and synaptic plasticity require changes in gene expression and yet can occur in a synapse-specific manner. This study provides evidence that a mechanism that mediates this gene expression during neuronal plasticity involves regulated translation of localized mRNA at stimulated synapses. These findings are instrumental in establishing the molecular processes involved in long-term memory formation and provide insight into diseases involving memory impairment.
This study was funded by the National Institutes of Health, the WM Keck Foundation and the Canadian Institutes of Health Research.
The finding provides the first visual evidence that when a new memory is formed new proteins are made locally at the synapse - the connection between nerve cells - increasing the strength of the synaptic connection and reinforcing the memory. The study published in Science, is important for understanding how memory traces are created and the ability to monitor it in real time will allow a detailed understanding of how memories are formed.
When considering what might be going on in the brain at a molecular level two essential properties of memory need to be taken into account. First, because a lot of information needs to be maintained over a long time there has to be some degree of stability. Second, to allow for learning and adaptation the system also needs to be highly flexible. For this reason, research has focused on synapses which are the main site of exchange and storage in the brain. They form a vast but also constantly fluctuating network of connections whose ability to change and adapt, called synaptic plasticity, may be the fundamental basis of learning and memory. "But, if this network is constantly changing, the question is how do memories stay put, how are they formed? It has been known for some time that an important step in long-term memory formation is "translation", or the production, of new proteins locally at the synapse, strengthening the synaptic connection in the reinforcement of a memory, which until now has never been imaged," says Dr. Wayne Sossin, neuroscientist at The Neuro and co-investigator in the study. "Using a translational reporter, a fluorescent protein that can be easily detected and tracked, we directly visualized the increased local translation, or protein synthesis, during memory formation. Importantly, this translation was synapse-specific and it required activation of the post-synaptic cell, showing that this step required cooperation between the pre and post-synaptic compartments, the parts of the two neurons that meet at the synapse. Thus highly regulated local translation occurs at synapses during long-term plasticity and requires trans-synaptic signals."
Long-term memory and synaptic plasticity require changes in gene expression and yet can occur in a synapse-specific manner. This study provides evidence that a mechanism that mediates this gene expression during neuronal plasticity involves regulated translation of localized mRNA at stimulated synapses. These findings are instrumental in establishing the molecular processes involved in long-term memory formation and provide insight into diseases involving memory impairment.
This study was funded by the National Institutes of Health, the WM Keck Foundation and the Canadian Institutes of Health Research.
CSF Fluid Shows Alzheimer's Disease Deterioration Much Earlier
ScienceDaily (June 19, 2009) — It is possible to determine which patients run a high risk of developing Alzheimer’s disease and the dementia associated with it, even in patients with minimal memory impairment. This has been shown by recent research at the Sahlgrenska Academy.
The results have just been published in the medical journal Lancet Neurology. "The earlier we can catch Alzheimer’s disease, the more we can do for the patient. The disease is one that progresses slowly, and the pharmaceuticals that are currently available are only able to alleviate the symptoms", says Kaj Blennow, professor at the Sahlgrenska Academy.
Several biomarkers have been identified in recent years. Biomarkers are proteins that can be detected in the cerebrospinal fluid and used to diagnose Alzheimer’s disease. It is now clear that the typical pattern of biomarkers known as the "CSF AD profile" can be seen in the cerebrospinal fluid of patients even with very mild memory deficiencies, before these can be detected by other tests.
"The patients who had the typical changes in biomarker profile of the cerebrospinal fluid had a risk of deterioration that was 27 times higher than the control group. We could also see that all patients with mild cognitive impairment who deteriorated and developed Alzheimer’s disease had these changes in the biomarker profile of their cerebrospinal fluid", says Kaj Blennow.
The scientists were also able to show a relationship between the profile of biomarkers and other typical signs of the disease, such as the presence of the gene APOE e4 and atrophy of the hippocampus, which is the part of the brain cortex that controls memory. "Our discovery that an analysis of biomarkers in the cerebrospinal fluid can reveal Alzheimer’s disease at a very early stage will have major significance if the new type of pharmaceutical that can directly slow the progression of the disease proves to have a clinical effect. It is important in this case to start treatment before the changes in the brain have become too severe", says Kaj Blennow. The research is part of a European research project known as DESCRIPA. Samples from 168 patients from seven countries are included in the study.
Alzheimer’s disease is one of the most widespread diseases in Sweden, with more than 100,000 people being affected. The disease is caused by harmful changes to the nerve cells in the brain, and it principally affects memory. The disease often leads to early death. Alzheimer’s disease not only causes untold suffering for patients and their families, it also gives rise to enormous costs for society.
The results have just been published in the medical journal Lancet Neurology. "The earlier we can catch Alzheimer’s disease, the more we can do for the patient. The disease is one that progresses slowly, and the pharmaceuticals that are currently available are only able to alleviate the symptoms", says Kaj Blennow, professor at the Sahlgrenska Academy.
Several biomarkers have been identified in recent years. Biomarkers are proteins that can be detected in the cerebrospinal fluid and used to diagnose Alzheimer’s disease. It is now clear that the typical pattern of biomarkers known as the "CSF AD profile" can be seen in the cerebrospinal fluid of patients even with very mild memory deficiencies, before these can be detected by other tests.
"The patients who had the typical changes in biomarker profile of the cerebrospinal fluid had a risk of deterioration that was 27 times higher than the control group. We could also see that all patients with mild cognitive impairment who deteriorated and developed Alzheimer’s disease had these changes in the biomarker profile of their cerebrospinal fluid", says Kaj Blennow.
The scientists were also able to show a relationship between the profile of biomarkers and other typical signs of the disease, such as the presence of the gene APOE e4 and atrophy of the hippocampus, which is the part of the brain cortex that controls memory. "Our discovery that an analysis of biomarkers in the cerebrospinal fluid can reveal Alzheimer’s disease at a very early stage will have major significance if the new type of pharmaceutical that can directly slow the progression of the disease proves to have a clinical effect. It is important in this case to start treatment before the changes in the brain have become too severe", says Kaj Blennow. The research is part of a European research project known as DESCRIPA. Samples from 168 patients from seven countries are included in the study.
Alzheimer’s disease is one of the most widespread diseases in Sweden, with more than 100,000 people being affected. The disease is caused by harmful changes to the nerve cells in the brain, and it principally affects memory. The disease often leads to early death. Alzheimer’s disease not only causes untold suffering for patients and their families, it also gives rise to enormous costs for society.
Saturday, June 6, 2009
Snoring Associated With Sleep Apnea May Impair Brain Function
ScienceDaily (June 4, 2009) — It has been linked to learning impairment, stroke and premature death. Now UNSW research has found that snoring associated with sleep apnea may impair brain function more than previously thought.
Sufferers of obstructive sleep apnea experience similar changes in brain biochemistry as people who have had a severe stroke or who are dying, the research shows.
A study by UNSW Brain Sciences, published this month in the Journal of Cerebral Blood Flow and Metabolism, is the first to analyse – in a second-by-second timeframe – what is happening in the brains of sufferers as they sleep. Previous studies have focused on recreating oxygen impairment in awake patients.
“It used to be thought that apneic snoring had absolutely no acute effects on brain function but this is plainly not true,” said lead author of the study, New South Global Professor Caroline Rae.
Sleep apnea affects as many as one in four middle-aged men, with around three percent going on to experience a severe form of the condition characterised by extended pauses in breathing, repetitive asphyxia and sleep fragmentation.
Children with enlarged tonsils and adenoids are also affected, raising concerns of long-term cognitive damage.
Professor Rae and collaborators from Sydney University’s Woolcock Institute used magnetic resonance spectroscopy to study the brains of 13 men with severe, untreated, obstructive sleep apnea. They found that even a moderate degree of oxygen desaturation during the patients’ sleep had significant effects on the brain’s bioenergetic status.
“The findings show that lack of oxygen while asleep may be far more detrimental than when awake, possibly because the normal compensatory mechanisms don't work as well when you are asleep,” Professor Rae, who is based at the Prince of Wales Medical Research Institute, said.
“This is happening in someone with sleep apnea acutely and continually when they are asleep. It’s a completely different biochemical mechanism from anything we’ve seen
before and is similar to what you see in somebody who has had a very severe stroke or is dying.”
The findings suggested societal perceptions of snoring needed to change, Professor Rae said.
“People look at people snoring and think it’s funny. That has to stop.”
Professor Rae said it was still unclear why the body responded to oxygen depletion in this way. It could be a form of ischemic preconditioning at work, much like in heart attack sufferers whose initial attack makes them more protected from subsequent attacks.
“The brain could be basically resetting its bioenergetics to make itself more resistant to lack of oxygen,” Professor Rae said. “It may be a compensatory mechanism to keep you alive, we just don’t know, but even if it is it’s not likely to be doing you much good.”
Sufferers of obstructive sleep apnea experience similar changes in brain biochemistry as people who have had a severe stroke or who are dying, the research shows.
A study by UNSW Brain Sciences, published this month in the Journal of Cerebral Blood Flow and Metabolism, is the first to analyse – in a second-by-second timeframe – what is happening in the brains of sufferers as they sleep. Previous studies have focused on recreating oxygen impairment in awake patients.
“It used to be thought that apneic snoring had absolutely no acute effects on brain function but this is plainly not true,” said lead author of the study, New South Global Professor Caroline Rae.
Sleep apnea affects as many as one in four middle-aged men, with around three percent going on to experience a severe form of the condition characterised by extended pauses in breathing, repetitive asphyxia and sleep fragmentation.
Children with enlarged tonsils and adenoids are also affected, raising concerns of long-term cognitive damage.
Professor Rae and collaborators from Sydney University’s Woolcock Institute used magnetic resonance spectroscopy to study the brains of 13 men with severe, untreated, obstructive sleep apnea. They found that even a moderate degree of oxygen desaturation during the patients’ sleep had significant effects on the brain’s bioenergetic status.
“The findings show that lack of oxygen while asleep may be far more detrimental than when awake, possibly because the normal compensatory mechanisms don't work as well when you are asleep,” Professor Rae, who is based at the Prince of Wales Medical Research Institute, said.
“This is happening in someone with sleep apnea acutely and continually when they are asleep. It’s a completely different biochemical mechanism from anything we’ve seen
before and is similar to what you see in somebody who has had a very severe stroke or is dying.”
The findings suggested societal perceptions of snoring needed to change, Professor Rae said.
“People look at people snoring and think it’s funny. That has to stop.”
Professor Rae said it was still unclear why the body responded to oxygen depletion in this way. It could be a form of ischemic preconditioning at work, much like in heart attack sufferers whose initial attack makes them more protected from subsequent attacks.
“The brain could be basically resetting its bioenergetics to make itself more resistant to lack of oxygen,” Professor Rae said. “It may be a compensatory mechanism to keep you alive, we just don’t know, but even if it is it’s not likely to be doing you much good.”
Discoveries Shed New LIght On How the Brain Processes What The Eye Sees
ScienceDaily (June 4, 2009) — Researchers at the Center for Molecular and Behavioral Neuroscience (CMBN) at Rutgers University in Newark have identified the need to develop a new framework for understanding “perceptual stability” and how we see the world with their discovery that visual input obtained during eye movements is being processed by the brain but blocked from awareness.
The process of seeing requires the eyes to move so light can hit the photoreceptors at the center of each retina, which then pass that information to the brain. If we were cognizant of the stimulus that passes before the eyes during the two to three times they move every second, however, vision would consist of a series of sensations of rapid motion rather than a stable perception of the world. To achieve perceptual stability, current theory has held that visual information gained during an eye movement is eliminated, as if cut off by a camera’s shutter, and removed from processing.
As published in Current Biology significant new research conducted by assistant professor Bart Krekelberg and post-doctoral researcher Tamara L. Watson now shows that theory of saccadic suppression is incorrect and what the brain is doing instead is processing information gained during eye movement but blocking it from being reported.
“Rather than completely suppressing inputs during eye movements, the brain is processing that as information it does not need to report back to awareness,” says Krekelberg.
The findings were obtained by making use of a visual illusion in which the presentation of a horizontal line makes a subsequent circle look like an ellipse. In Watson and Krekelberg’s study, the line was presented to research participants immediately before an eye movement. Under current theory, the line would be eliminated from visual processing and one would expect participants to report a subsequently presented circle to look like a circle. While the research participants did not recall seeing the line, the image they reported seeing was not a circle but rather an ellipse. In other words, the participants experienced the illusion, even though they were not aware of the line that causes the illusion.
“Although they did not recall seeing the line, the brain apparently did process the line,” says Watson. “What this shows is that perceptual stability is not accomplished by suppressing stimuli encountered during an eye movement, or removing them from processing, but rather that those signals are prevented from reaching awareness at a later stage of processing. Some suppression is also happening, but suppression is not enough to explain perceptual stability; it is not the whole story.”
One reason why the brain does not discard visual input during eye movements could be that it provides useful information about eye movements. “We speculate that the visual signals generated by eye movement may be important for determining how much and how fast the eye moved so the brain can maintain perceptual stability,” says Watson. “It may be that these signals are useful for improving perceptual stability as long as they do not enter into awareness.”
The findings also show that a new approach is needed to gain additional understanding into the cognitive and neural functions involved in visual processing and perceptual stability. Until now, research largely has focused on pinpointing those areas of the brain that show lower activity during an eye movement. “What we are seeing now is that things are much more complex than we suspected,” says Krekelberg. “We shouldn’t just be looking at areas of reduced activity in the brain during eye movement, but for areas that may change their processing to make use of the input that arises during eye movements.”
Providing a better understanding of those changes in processing could pave the way for earlier detection and more effective treatments for those who suffer from deficits associated with eye movements. For example, schizophrenic patients sometimes report a lack of perceptual stability. And while dyslexia traditionally has been interpreted as a deficit in language development, it also has been found to be associated with deficits in the control of eye movements.
The research was supported by a fellowship to Tamara Watson from the Human Frontiers Science Program and a scholarship to Bart Krekelberg from the Pew Charitable Trusts.
The process of seeing requires the eyes to move so light can hit the photoreceptors at the center of each retina, which then pass that information to the brain. If we were cognizant of the stimulus that passes before the eyes during the two to three times they move every second, however, vision would consist of a series of sensations of rapid motion rather than a stable perception of the world. To achieve perceptual stability, current theory has held that visual information gained during an eye movement is eliminated, as if cut off by a camera’s shutter, and removed from processing.
As published in Current Biology significant new research conducted by assistant professor Bart Krekelberg and post-doctoral researcher Tamara L. Watson now shows that theory of saccadic suppression is incorrect and what the brain is doing instead is processing information gained during eye movement but blocking it from being reported.
“Rather than completely suppressing inputs during eye movements, the brain is processing that as information it does not need to report back to awareness,” says Krekelberg.
The findings were obtained by making use of a visual illusion in which the presentation of a horizontal line makes a subsequent circle look like an ellipse. In Watson and Krekelberg’s study, the line was presented to research participants immediately before an eye movement. Under current theory, the line would be eliminated from visual processing and one would expect participants to report a subsequently presented circle to look like a circle. While the research participants did not recall seeing the line, the image they reported seeing was not a circle but rather an ellipse. In other words, the participants experienced the illusion, even though they were not aware of the line that causes the illusion.
“Although they did not recall seeing the line, the brain apparently did process the line,” says Watson. “What this shows is that perceptual stability is not accomplished by suppressing stimuli encountered during an eye movement, or removing them from processing, but rather that those signals are prevented from reaching awareness at a later stage of processing. Some suppression is also happening, but suppression is not enough to explain perceptual stability; it is not the whole story.”
One reason why the brain does not discard visual input during eye movements could be that it provides useful information about eye movements. “We speculate that the visual signals generated by eye movement may be important for determining how much and how fast the eye moved so the brain can maintain perceptual stability,” says Watson. “It may be that these signals are useful for improving perceptual stability as long as they do not enter into awareness.”
The findings also show that a new approach is needed to gain additional understanding into the cognitive and neural functions involved in visual processing and perceptual stability. Until now, research largely has focused on pinpointing those areas of the brain that show lower activity during an eye movement. “What we are seeing now is that things are much more complex than we suspected,” says Krekelberg. “We shouldn’t just be looking at areas of reduced activity in the brain during eye movement, but for areas that may change their processing to make use of the input that arises during eye movements.”
Providing a better understanding of those changes in processing could pave the way for earlier detection and more effective treatments for those who suffer from deficits associated with eye movements. For example, schizophrenic patients sometimes report a lack of perceptual stability. And while dyslexia traditionally has been interpreted as a deficit in language development, it also has been found to be associated with deficits in the control of eye movements.
The research was supported by a fellowship to Tamara Watson from the Human Frontiers Science Program and a scholarship to Bart Krekelberg from the Pew Charitable Trusts.
Tuesday, May 26, 2009
A Brain Disorder Easily Missed Or Misdiagnosed As Alzheimer's or Parkinsons
Tomorrow's *New York Times* (Tuesday, May 26) includes an article: "ABrain Disorder Easily Missed" by Jane Brody.Here are some excerpts:
Edward Ferguson, a civil engineer living in Vancouver, Wash., retired atage 65 from a job handling multimillion-dollar contracts.Five years later he could not balance a checkbook, walk without falling,drive a car, control his bladder or recognize his granddaughter.Instead of the active retirement he had anticipated, Mr. Ferguson, now74, thought he would spend the rest of his life in a wheelchair,incontinent and struggling with dementia.
Ten doctors were unable to tell him what was wrong, but an Internetsearch by his daughter found a condition that seemed to match hissymptoms: normal pressure hydrocephalus, or N.P.H.
The disorder involves a build-up of spinal fluid in the ventricles ofthe brain, causing pressure on nerves that control the legs, balance,bladder and cognitive function."It's as if the brain has reverted to babyhood," Dr. Michael Kaplitt, aneurosurgeon at NewYork-Presbyterian Hospital/Weill Cornell MedicalCenter, said in an interview."Like babies, people with N.P.H. walk slowly with feet wide apart, theyare incontinent and have no memory."Dr. Kaplitt calls it "a classic triad of symptoms" that should alertdoctors to the possibility of N.P.H.Yet the condition is frequently misdiagnosed as dementia, Alzheimer'sdisease, Parkinson's disease or a spinal problem.Or it is attributed to age -- nearly all who are affected are over 55.
Two days after surgery to install a programmable shunt that relieved thepressure on the frontal lobes of his brain, Mr. Ferguson walked across aroom for the first time in a year.He was able to think and write clearly, and his incontinence improved.The Fergusons are now looking forward to their 56th anniversary. Mr.Ferguson, who had contemplated suicide, considers himself to have asecond chance at life."At one point I saw no light at the end of the tunnel," he said, "andnow it is just so beautiful there."
No one knows how often N.P.H. occurs because it is so often missed ormisdiagnosed. Estimates range from 50,000 to 375,000 people in theUnited States, with the higher figure more likely to be correct, saidDr. Mark Luciano, a neurosurgeon at the Cleveland Clinic."There are a lot of people out there with a correctable problem that isattributed to old age," Dr. Luciano said."When the problem is fixed, it's like rescuing them from oblivion.A small percentage of people with dementia -- maybe 10 or 15 percent --really have N.P.H."The disorder was recognized and named in 1965.But most doctors who treat older people are unaware of it or fail tothink of it when treating patients with classic, albeit confusing, symptoms.
Normal pressure hydrocephalus is best diagnosed by a team that includesa radiologist, neuropsychologist and neurologist or neurosurgeonexperienced in distinguishing this condition.
The best clue often comes from a careful medical history, since N.P.H.typically starts with gait problems, Dr. Luciano and his colleague, Dr.Ronan Factora, a geriatrician at the Cleveland Clinic, reported lastyear in the journal Geriatrics.Cognitive impairment typically does not precede gait problems, theysaid, but when it does, or when dementia has become severe, the responseto treatment is lessened. Incontinence, which starts out as urinary urgency, can occur at any pointin the disease, and is often worsened by problems with walking or dementia.
Although there is no one route to diagnosis, if N.P.H. is suspected, aCT scan or M.R.I. of the brain can reveal one or more enlargedventricles, an essential feature of the condition.On an M.R.I., Dr. Kaplitt said, the spinal fluid often is cloudy or turbulent.Treating N.P.H. involves inserting a shunt into the brain to drain offaccumulating spinal fluid and divert it to the abdomen, where it can bereabsorbed into the bloodstream.The ideal shunt has a valve and can be reprogrammed to regulate the drainage.Repeat surgery is a possibility if the shunt drains off too much or toolittle spinal fluid.While the shunt is not a cure for N.P.H., in the 70 to 80 percent ofpatients who benefit from it, it may give them a decade or more of near-normal life, the experts said
Edward Ferguson, a civil engineer living in Vancouver, Wash., retired atage 65 from a job handling multimillion-dollar contracts.Five years later he could not balance a checkbook, walk without falling,drive a car, control his bladder or recognize his granddaughter.Instead of the active retirement he had anticipated, Mr. Ferguson, now74, thought he would spend the rest of his life in a wheelchair,incontinent and struggling with dementia.
Ten doctors were unable to tell him what was wrong, but an Internetsearch by his daughter found a condition that seemed to match hissymptoms: normal pressure hydrocephalus, or N.P.H.
The disorder involves a build-up of spinal fluid in the ventricles ofthe brain, causing pressure on nerves that control the legs, balance,bladder and cognitive function."It's as if the brain has reverted to babyhood," Dr. Michael Kaplitt, aneurosurgeon at NewYork-Presbyterian Hospital/Weill Cornell MedicalCenter, said in an interview."Like babies, people with N.P.H. walk slowly with feet wide apart, theyare incontinent and have no memory."Dr. Kaplitt calls it "a classic triad of symptoms" that should alertdoctors to the possibility of N.P.H.Yet the condition is frequently misdiagnosed as dementia, Alzheimer'sdisease, Parkinson's disease or a spinal problem.Or it is attributed to age -- nearly all who are affected are over 55.
Two days after surgery to install a programmable shunt that relieved thepressure on the frontal lobes of his brain, Mr. Ferguson walked across aroom for the first time in a year.He was able to think and write clearly, and his incontinence improved.The Fergusons are now looking forward to their 56th anniversary. Mr.Ferguson, who had contemplated suicide, considers himself to have asecond chance at life."At one point I saw no light at the end of the tunnel," he said, "andnow it is just so beautiful there."
No one knows how often N.P.H. occurs because it is so often missed ormisdiagnosed. Estimates range from 50,000 to 375,000 people in theUnited States, with the higher figure more likely to be correct, saidDr. Mark Luciano, a neurosurgeon at the Cleveland Clinic."There are a lot of people out there with a correctable problem that isattributed to old age," Dr. Luciano said."When the problem is fixed, it's like rescuing them from oblivion.A small percentage of people with dementia -- maybe 10 or 15 percent --really have N.P.H."The disorder was recognized and named in 1965.But most doctors who treat older people are unaware of it or fail tothink of it when treating patients with classic, albeit confusing, symptoms.
Normal pressure hydrocephalus is best diagnosed by a team that includesa radiologist, neuropsychologist and neurologist or neurosurgeonexperienced in distinguishing this condition.
The best clue often comes from a careful medical history, since N.P.H.typically starts with gait problems, Dr. Luciano and his colleague, Dr.Ronan Factora, a geriatrician at the Cleveland Clinic, reported lastyear in the journal Geriatrics.Cognitive impairment typically does not precede gait problems, theysaid, but when it does, or when dementia has become severe, the responseto treatment is lessened. Incontinence, which starts out as urinary urgency, can occur at any pointin the disease, and is often worsened by problems with walking or dementia.
Although there is no one route to diagnosis, if N.P.H. is suspected, aCT scan or M.R.I. of the brain can reveal one or more enlargedventricles, an essential feature of the condition.On an M.R.I., Dr. Kaplitt said, the spinal fluid often is cloudy or turbulent.Treating N.P.H. involves inserting a shunt into the brain to drain offaccumulating spinal fluid and divert it to the abdomen, where it can bereabsorbed into the bloodstream.The ideal shunt has a valve and can be reprogrammed to regulate the drainage.Repeat surgery is a possibility if the shunt drains off too much or toolittle spinal fluid.While the shunt is not a cure for N.P.H., in the 70 to 80 percent ofpatients who benefit from it, it may give them a decade or more of near-normal life, the experts said
Sunday, May 24, 2009
Alzheimer's Discovery Could Bring Early Diagnosis and Treatment Closer
ScienceDaily (May 23, 2009) — A discovery made by researchers at McGill University and the affiliated Lady Davis Research Institute for Medical Research at Montreal's Jewish General Hospital offers new hope for the early diagnosis and treatment of Alzheimer's disease.
In a study published in the Journal of Biological Chemistry on May 15, Dr. Hemant Paudel, his PhD student Dong Han and postdoctoral fellows Hamid Qureshi and Yifan Lu, report that the addition of a single phosphate to an amino acid in a key brain protein is a principal cause of Alzheimer's.
Identifying this phosphate, one of up to two-dozen such molecules, could make earlier diagnosis of Alzheimer's possible and might, in the longer term, lead to the development of drugs to block its onset.
The crucial protein, called a tau protein, is a normal part of the brain and central nervous system. But in Alzheimer's patients, tau proteins go out of control and form tangles that, along with senile plaques, are the primary cause of the degenerative disease.
Several years ago, it was discovered that tau proteins in normal brains contain only three to four attached phosphates, while abnormal tau in Alzheimer's patients have anywhere from 21 to 25 additional phosphates.
Paudel and his team have discovered that it is the addition of a single phosphate to the Ser202 amino acid within the tau brain protein that is the principal culprit responsible for Alzheimer's.
"The impact of this study is twofold," said Paudel, associate professor at McGill's Dept. of Neurology and Neurosurgery, and Project Director at the Bloomfield Centre for Research in Aging at the Lady Davis. "We can now do brain imaging at the earliest stages of the disease. We don't have to look for many different tau phosphates, just this single phosphate. The possibility of early diagnosis now exists.
"Second, the enzyme which puts this phosphate on the tau can be targeted by drugs, so therapies can be developed. This discovery gives us, for the first time, a clear direction towards the early diagnosis and treatment of Alzheimer's."
Paudel and his students worked for years to exclude the phosphates not directly responsible for causing Alzheimer's symptoms. They finally succeeded by working with FTDP-17, a genetic disease with symptoms similar to Alzheimer's, but transmitted via mutations. By genetically manipulating these mutations, they were able to prove that the phosphate on Ser202 almost single-handedly is responsible for the tau abnormalities that cause both FTDP-17 and Alzheimer's.
The disease leads to severe mental degeneration and almost-inevitable death, and there is no known cure, nor even a reliable technique for early diagnosis. A patient is diagnosed with advanced Alzheimer's in the United States every 70 seconds, and deaths due to the disease have increased by a staggering 47 per cent since 2000. With the Baby Boomer population aging, those numbers are expected to explode even further in coming decades.
There are more than 5.3 million people with Alzheimer's in the United States, and more than 300,000 in Canada. Every one of those patients faces years of increasing mental incapacity followed by almost certain death, with no hope of treatment. The U.S. Alzheimer's Association has called the current situation a "crisis."
In a study published in the Journal of Biological Chemistry on May 15, Dr. Hemant Paudel, his PhD student Dong Han and postdoctoral fellows Hamid Qureshi and Yifan Lu, report that the addition of a single phosphate to an amino acid in a key brain protein is a principal cause of Alzheimer's.
Identifying this phosphate, one of up to two-dozen such molecules, could make earlier diagnosis of Alzheimer's possible and might, in the longer term, lead to the development of drugs to block its onset.
The crucial protein, called a tau protein, is a normal part of the brain and central nervous system. But in Alzheimer's patients, tau proteins go out of control and form tangles that, along with senile plaques, are the primary cause of the degenerative disease.
Several years ago, it was discovered that tau proteins in normal brains contain only three to four attached phosphates, while abnormal tau in Alzheimer's patients have anywhere from 21 to 25 additional phosphates.
Paudel and his team have discovered that it is the addition of a single phosphate to the Ser202 amino acid within the tau brain protein that is the principal culprit responsible for Alzheimer's.
"The impact of this study is twofold," said Paudel, associate professor at McGill's Dept. of Neurology and Neurosurgery, and Project Director at the Bloomfield Centre for Research in Aging at the Lady Davis. "We can now do brain imaging at the earliest stages of the disease. We don't have to look for many different tau phosphates, just this single phosphate. The possibility of early diagnosis now exists.
"Second, the enzyme which puts this phosphate on the tau can be targeted by drugs, so therapies can be developed. This discovery gives us, for the first time, a clear direction towards the early diagnosis and treatment of Alzheimer's."
Paudel and his students worked for years to exclude the phosphates not directly responsible for causing Alzheimer's symptoms. They finally succeeded by working with FTDP-17, a genetic disease with symptoms similar to Alzheimer's, but transmitted via mutations. By genetically manipulating these mutations, they were able to prove that the phosphate on Ser202 almost single-handedly is responsible for the tau abnormalities that cause both FTDP-17 and Alzheimer's.
The disease leads to severe mental degeneration and almost-inevitable death, and there is no known cure, nor even a reliable technique for early diagnosis. A patient is diagnosed with advanced Alzheimer's in the United States every 70 seconds, and deaths due to the disease have increased by a staggering 47 per cent since 2000. With the Baby Boomer population aging, those numbers are expected to explode even further in coming decades.
There are more than 5.3 million people with Alzheimer's in the United States, and more than 300,000 in Canada. Every one of those patients faces years of increasing mental incapacity followed by almost certain death, with no hope of treatment. The U.S. Alzheimer's Association has called the current situation a "crisis."
Tuesday, May 12, 2009
Women More Likely To Experience Non-Traditional Stroke Symptoms
ScienceDaily (May 12, 2009) — The traditional stroke symptoms are well known and include a sudden onset of numbness or weakness on one side of the body, trouble talking, loss of vision, or coordination problems.
But in women, doctors and bystanders should be paying attention to something else, says Lynda Lisabeth, Ph.D., MPH, researcher in the department of neurology at the University of Michigan Health System.
“What we’re finding is that women experience what is considered non-traditional symptoms,” said Lisabeth, who presented research findings on acute stroke symptoms at the 2009 International Stroke Conference this spring. “The non-traditional symptom that stood out was altered mental status, meaning confusion, disorientation or a loss of consciousness.”
Symptoms such as sudden numbness of the face, arm or leg are a warning sign of what’s happening in the body during a stroke which is a loss of blood supply to the brain because of a blocked or ruptured artery.
While larger scale studies focusing on stroke in women are warranted, the gender differences U-M researchers identified may contribute to delay in treatment for women and could signal a need to change public health campaigns, Lisabeth says.
The U-M study examined ischemic strokes, the kind experienced by 80 percent of stroke victims, and transient ischemic attack, called mini-strokes because symptoms go away quickly. Researchers examined the cases of 461 men and women and classified their symptoms as either traditional or non-traditional.
Altered mental status was the most common non-traditional symptom and it was more likely to be reported in women, the study showed. Researchers do not know why women’s symptoms were different.
But the differences in symptoms may have consequences if slow recognition of stroke signs cause a delay in treatment, the researcher says.
“The only treatment that is currently FDA approved in the United States for stroke is tPA (tissue plasminogen activator), or what we call a clot-busting drug,” Lisabeth says. “To administer tPA, people with stroke have to get to the hospital within three hours of symptom onset. So any delay on the part of actually getting to the hospital or delays once at the hospital could literally mean the difference between getting the therapy, or not getting the therapy.”
Each year 800,000 Americans experience a stroke. Hispanic Americans and African Americans have a greater risk having a stroke, and to die from it. Intensive rehabilitation can help some overcome loss of function, but stroke remains a leading cause of disability. It is the third leading cause of death.
Men have an increased risk of stroke across most age groups. But in the oldest age groups, women’s risk is higher, and since women live longer than men, women actually have an increased lifetime risk for stroke.
Several studies have suggested that women experience greater in-hospital delays such as longer triage times, longer time to see a physician and longer times to head imaging, which is critical for the diagnosis of stroke, compared with men, and have 30 percent lower odds of receiving tPA. Causes of these disparities are unclear, but could result from the different symptom presentation in women.
“We’re hoping to understand those clinical implications and that information may lend itself to targeting stroke public health messages to women so that they can understand what it means to have one of these non-traditional stroke symptoms, and again emphasizing the urgency to seek care,” says Lisabeth, who is also an assistant professor in the department of epidemiology in the U-M School of Public Health.
Recognizing an ischemic stroke
Strokes are a medical emergency, and if you notice one or more of these signs, don’t wait. Call 9-1-1, or emergency medical services.
Sudden numbness or weakness of the face, arm or leg, especially on one side of the body;
Sudden confusion, trouble speaking or understanding
Sudden trouble seeing in one or both eyes
Sudden trouble walking, dizziness, loss of balance or coordination
Sudden severe headache with no known cause.
But in women, doctors and bystanders should be paying attention to something else, says Lynda Lisabeth, Ph.D., MPH, researcher in the department of neurology at the University of Michigan Health System.
“What we’re finding is that women experience what is considered non-traditional symptoms,” said Lisabeth, who presented research findings on acute stroke symptoms at the 2009 International Stroke Conference this spring. “The non-traditional symptom that stood out was altered mental status, meaning confusion, disorientation or a loss of consciousness.”
Symptoms such as sudden numbness of the face, arm or leg are a warning sign of what’s happening in the body during a stroke which is a loss of blood supply to the brain because of a blocked or ruptured artery.
While larger scale studies focusing on stroke in women are warranted, the gender differences U-M researchers identified may contribute to delay in treatment for women and could signal a need to change public health campaigns, Lisabeth says.
The U-M study examined ischemic strokes, the kind experienced by 80 percent of stroke victims, and transient ischemic attack, called mini-strokes because symptoms go away quickly. Researchers examined the cases of 461 men and women and classified their symptoms as either traditional or non-traditional.
Altered mental status was the most common non-traditional symptom and it was more likely to be reported in women, the study showed. Researchers do not know why women’s symptoms were different.
But the differences in symptoms may have consequences if slow recognition of stroke signs cause a delay in treatment, the researcher says.
“The only treatment that is currently FDA approved in the United States for stroke is tPA (tissue plasminogen activator), or what we call a clot-busting drug,” Lisabeth says. “To administer tPA, people with stroke have to get to the hospital within three hours of symptom onset. So any delay on the part of actually getting to the hospital or delays once at the hospital could literally mean the difference between getting the therapy, or not getting the therapy.”
Each year 800,000 Americans experience a stroke. Hispanic Americans and African Americans have a greater risk having a stroke, and to die from it. Intensive rehabilitation can help some overcome loss of function, but stroke remains a leading cause of disability. It is the third leading cause of death.
Men have an increased risk of stroke across most age groups. But in the oldest age groups, women’s risk is higher, and since women live longer than men, women actually have an increased lifetime risk for stroke.
Several studies have suggested that women experience greater in-hospital delays such as longer triage times, longer time to see a physician and longer times to head imaging, which is critical for the diagnosis of stroke, compared with men, and have 30 percent lower odds of receiving tPA. Causes of these disparities are unclear, but could result from the different symptom presentation in women.
“We’re hoping to understand those clinical implications and that information may lend itself to targeting stroke public health messages to women so that they can understand what it means to have one of these non-traditional stroke symptoms, and again emphasizing the urgency to seek care,” says Lisabeth, who is also an assistant professor in the department of epidemiology in the U-M School of Public Health.
Recognizing an ischemic stroke
Strokes are a medical emergency, and if you notice one or more of these signs, don’t wait. Call 9-1-1, or emergency medical services.
Sudden numbness or weakness of the face, arm or leg, especially on one side of the body;
Sudden confusion, trouble speaking or understanding
Sudden trouble seeing in one or both eyes
Sudden trouble walking, dizziness, loss of balance or coordination
Sudden severe headache with no known cause.
Monday, May 11, 2009
Memory For Different Smells: Synaptic Memory Found In Olfactory Bulb
ScienceDaily (May 9, 2009) — Ben W. Strowbridge, Ph.D, associate professor of Neuroscience and Physiology/Biophysics, and Yuan Gao, a Ph.D. student in the neurosciences program at Case Western Reserve University School of Medicine, are the first to discover a form of synaptic memory in the olfactory bulb, the part of the brain that processes the sense of smell.
In the 1970s, scientists discovered that elemental connections between brain cells, called synapses, could change their strength following brief periods of activity. This process, called long-term potentiation (LTP), is the leading candidate to explain how we store information about specific places, names and events. While laboratories around the world have found LTP in nearly every part of the mammalian brain there was one glaring exception: the part of the brain that first processes the sense of smell, the olfactory bulb.
Gao, a fourth-year graduate student, had learned that damaging olfactory sensory pathways prevents sheep from forming selective bonds with her own lambs, causing them to adopt lambs from other mothers. This cued her curiosity as to how a mother ewe forms such a selective bond with her lamb within several hours of parturition, a bond that is primarily dependent on olfactory sensory recognition.
Using an innovative home-built laser microscope, Strowbridge and Gao were able to determine that the olfactory bulb does in fact have LTP. This specialized microscope used an advanced imaging technique called "2-photon excitation" which enabled the researchers to see entire brain cells and then test whether different types of inputs to the cell could mediate olfactory memory.
"The real surprise in the study was the specific brain connection that changed following experience. It was a rarely-studied brain projection from the cortex back to the olfactory bulb" said Strowbridge.
Neuroscientists commonly believe that the way the brain processes information is similar to climbing a pyramid—starting from the bottom and working up to the top. All of the sensory systems have a large number of low-level cells that do very simple things (forming the base of the pyramid), and then they feed their results to brain areas higher up the pyramid. The brain cells in these "higher" regions begin to reflect abstract concepts, such as the shape of human faces, in the visual system or melodies in the auditory system. The brain areas related to our conscious perception of the world are presumably at the top of pyramid.
However, the Case Western Reserve University researchers found that the brain circuit had the ability to change with experience was unexpectedly a connection from high in the pyramid (the olfactory cortex) back to a lower level (the olfactory bulb).
One of the implications of Strowbridge and Gao's work is that the brain may learn about different smells by having higher brain areas first make a prediction about which scent it might be, and then test that prediction against the actual sensory data coming into the brain.
"Our work suggests that there is much more talking back-and-forth between higher and lower brain areas during olfactory learning," continued Strowbridge. "We are just beginning to explore the function of the feedback circuits that inform low-level parts of the brain, like the olfactory bulb, about predictions made by higher-order brain regions. The 2-photon microscope used in this study is an ideal tool to ask what these different brain circuits are actually doing."
Previous studies had suggested that the circuit changes associated with olfactory learning, such as sheep learning to recognize their own lambs though their characteristic scents, involved changes in the olfactory bulb. Strowbridge and Gao discovered that certain olfactory brain circuits can change with experience. This discovery provides a possible explanation for how animals can form memories of particular scents.
In 2006, Strowbridge's grouped discovered a new type of brain cell, the Blanes cell, in the olfactory bulb, also using the same home-built 2-photon microscope. Ramón y Cajal, an important Spanish anatomist, had drawn pictures of these cells and named them for one of his medical students in the late 1800s. They stayed a curiosity item in very old textbooks until Strowbridge's laboratory found that they represented a very important cell type in the brain. Using 2-photon imaging, the CWRU group showed that Blanes cells have unusual properties that may help the brain maintain memories of smells and also opened a new approach to understanding the basis of memory impairment in Alzheimer's disease. That study was published in the March 16, 2006 issue of the journal Neuron.
This study was funded by the National Institutes of Health. The 2-photon laser microscope used in the study was constructed with support from the Mount Sinai Health Care Foundation.
In the 1970s, scientists discovered that elemental connections between brain cells, called synapses, could change their strength following brief periods of activity. This process, called long-term potentiation (LTP), is the leading candidate to explain how we store information about specific places, names and events. While laboratories around the world have found LTP in nearly every part of the mammalian brain there was one glaring exception: the part of the brain that first processes the sense of smell, the olfactory bulb.
Gao, a fourth-year graduate student, had learned that damaging olfactory sensory pathways prevents sheep from forming selective bonds with her own lambs, causing them to adopt lambs from other mothers. This cued her curiosity as to how a mother ewe forms such a selective bond with her lamb within several hours of parturition, a bond that is primarily dependent on olfactory sensory recognition.
Using an innovative home-built laser microscope, Strowbridge and Gao were able to determine that the olfactory bulb does in fact have LTP. This specialized microscope used an advanced imaging technique called "2-photon excitation" which enabled the researchers to see entire brain cells and then test whether different types of inputs to the cell could mediate olfactory memory.
"The real surprise in the study was the specific brain connection that changed following experience. It was a rarely-studied brain projection from the cortex back to the olfactory bulb" said Strowbridge.
Neuroscientists commonly believe that the way the brain processes information is similar to climbing a pyramid—starting from the bottom and working up to the top. All of the sensory systems have a large number of low-level cells that do very simple things (forming the base of the pyramid), and then they feed their results to brain areas higher up the pyramid. The brain cells in these "higher" regions begin to reflect abstract concepts, such as the shape of human faces, in the visual system or melodies in the auditory system. The brain areas related to our conscious perception of the world are presumably at the top of pyramid.
However, the Case Western Reserve University researchers found that the brain circuit had the ability to change with experience was unexpectedly a connection from high in the pyramid (the olfactory cortex) back to a lower level (the olfactory bulb).
One of the implications of Strowbridge and Gao's work is that the brain may learn about different smells by having higher brain areas first make a prediction about which scent it might be, and then test that prediction against the actual sensory data coming into the brain.
"Our work suggests that there is much more talking back-and-forth between higher and lower brain areas during olfactory learning," continued Strowbridge. "We are just beginning to explore the function of the feedback circuits that inform low-level parts of the brain, like the olfactory bulb, about predictions made by higher-order brain regions. The 2-photon microscope used in this study is an ideal tool to ask what these different brain circuits are actually doing."
Previous studies had suggested that the circuit changes associated with olfactory learning, such as sheep learning to recognize their own lambs though their characteristic scents, involved changes in the olfactory bulb. Strowbridge and Gao discovered that certain olfactory brain circuits can change with experience. This discovery provides a possible explanation for how animals can form memories of particular scents.
In 2006, Strowbridge's grouped discovered a new type of brain cell, the Blanes cell, in the olfactory bulb, also using the same home-built 2-photon microscope. Ramón y Cajal, an important Spanish anatomist, had drawn pictures of these cells and named them for one of his medical students in the late 1800s. They stayed a curiosity item in very old textbooks until Strowbridge's laboratory found that they represented a very important cell type in the brain. Using 2-photon imaging, the CWRU group showed that Blanes cells have unusual properties that may help the brain maintain memories of smells and also opened a new approach to understanding the basis of memory impairment in Alzheimer's disease. That study was published in the March 16, 2006 issue of the journal Neuron.
This study was funded by the National Institutes of Health. The 2-photon laser microscope used in the study was constructed with support from the Mount Sinai Health Care Foundation.
New Evidence Ties Gene To Alzheimer's
ScienceDaily (May 8, 2009) — Of dozens of candidates potentially involved in increasing a person's risk for the most common type of Alzheimer's disease that affects more than 5 million Americans over the age of 65, one gene that keeps grabbing Johns Hopkins researchers' attention makes a protein called neuroglobin.
Adding to a growing body of evidence about the importance of this protein for the health of the aging brain, researchers at the McKusick-Nathans Institute of Genetic Medicine of the Johns Hopkins University School of Medicine canvassed the genetic neighborhood of neuroglobin and, for the first time in a human population, linked variation there with a risk for Alzheimer's.
Ever so slight genetic variations between individuals can and do influence the amounts of particular proteins that each specific gene ultimately produces. In this case, the team has found that individuals with genetic variations equating to less neuroglobin production have an increased risk for Alzheimer's.
"An intriguing part of this study was the high levels of neuroglobin that we found in the Alzheimer's brain, which was exactly the opposite from what we expected," says Dimitrios Avramopoulos, M.D., Ph.D., an associate professor in Hopkins' Institute of Genetic Medicine and the Department of Psychiatry.
Referring to data published in Neurobiology of Aging, Avramopoulos explains that his team measured levels of gene product in 56 different samples of human brain tissue: 30 from confirmed cases of Alzheimer's and 26 without brain disease.
The scientists found that neuroglobin levels decreased with advancing age, which, Avramopoulos points out, is consistent with risk of Alzheimer's increasing with advancing age. They also found that levels of neuroglobin were lower in women than in men, which is consistent with the fact that women have a slightly higher risk of Alzheimer's. About two times as many patients in the general population with Alzheimer's are women which, in part, can be attributed to the fact that women live longer and therefore have more of a chance to get Alzheimer's.
Having corrected for that disparity, researchers have noted a slightly higher risk in women than in men.
They were surprised to find that neuroglobin levels were higher in the brain tissue from Alzheimer's patients than that of the control group.
Counter-intuitive though it seemed at first, it actually makes sense, Avramopoulos says, especially in light of previously published studies that indicated a protective function for neuroglobin and showed that mouse brains respond to stress — in this case, a lack of oxygen — by producing more neuroglobin.
The scientists think that neuroglobin production also ramps up in reaction to the insult of the Alzheimer's disease. They hypothesize that maybe in some people it's simply not enough of a protective response to effectively defend the brain.
"The older we get, the less neuroglobin this particular gene produces in our brains — unless something stimulates the gene to produce more," Avramopoulos explains. "That something could be a stressor such as a lack of oxygen resulting from stoke or emphysema, for instance. And it looks like it also could be Alzheimer's disease.
"Further work on this gene will likely provide intervention targets for a multitude of very common conditions including Alzheimer's."
In addition to Avramopoulos, authors of the paper are Megan Szymanski, Ruihua Wang, M. Danielle Fallin and Susan S. Bassett, all of Johns Hopkins.
Journal reference:
Megan Szymanski, Ruihua Wang, M. Danielle Fallin, Susan S. Bassett, Dimitrios Avramopoulos. Neuroglobin and Alzheimer's dementia: Genetic association and gene expression changes. Neurobiology of Aging, 2008; DOI: 10.1016/j.neurobiolaging.2008.10.003
Adapted from materials provided by Johns Hopkins Medical Institutions.
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Adding to a growing body of evidence about the importance of this protein for the health of the aging brain, researchers at the McKusick-Nathans Institute of Genetic Medicine of the Johns Hopkins University School of Medicine canvassed the genetic neighborhood of neuroglobin and, for the first time in a human population, linked variation there with a risk for Alzheimer's.
Ever so slight genetic variations between individuals can and do influence the amounts of particular proteins that each specific gene ultimately produces. In this case, the team has found that individuals with genetic variations equating to less neuroglobin production have an increased risk for Alzheimer's.
"An intriguing part of this study was the high levels of neuroglobin that we found in the Alzheimer's brain, which was exactly the opposite from what we expected," says Dimitrios Avramopoulos, M.D., Ph.D., an associate professor in Hopkins' Institute of Genetic Medicine and the Department of Psychiatry.
Referring to data published in Neurobiology of Aging, Avramopoulos explains that his team measured levels of gene product in 56 different samples of human brain tissue: 30 from confirmed cases of Alzheimer's and 26 without brain disease.
The scientists found that neuroglobin levels decreased with advancing age, which, Avramopoulos points out, is consistent with risk of Alzheimer's increasing with advancing age. They also found that levels of neuroglobin were lower in women than in men, which is consistent with the fact that women have a slightly higher risk of Alzheimer's. About two times as many patients in the general population with Alzheimer's are women which, in part, can be attributed to the fact that women live longer and therefore have more of a chance to get Alzheimer's.
Having corrected for that disparity, researchers have noted a slightly higher risk in women than in men.
They were surprised to find that neuroglobin levels were higher in the brain tissue from Alzheimer's patients than that of the control group.
Counter-intuitive though it seemed at first, it actually makes sense, Avramopoulos says, especially in light of previously published studies that indicated a protective function for neuroglobin and showed that mouse brains respond to stress — in this case, a lack of oxygen — by producing more neuroglobin.
The scientists think that neuroglobin production also ramps up in reaction to the insult of the Alzheimer's disease. They hypothesize that maybe in some people it's simply not enough of a protective response to effectively defend the brain.
"The older we get, the less neuroglobin this particular gene produces in our brains — unless something stimulates the gene to produce more," Avramopoulos explains. "That something could be a stressor such as a lack of oxygen resulting from stoke or emphysema, for instance. And it looks like it also could be Alzheimer's disease.
"Further work on this gene will likely provide intervention targets for a multitude of very common conditions including Alzheimer's."
In addition to Avramopoulos, authors of the paper are Megan Szymanski, Ruihua Wang, M. Danielle Fallin and Susan S. Bassett, all of Johns Hopkins.
Journal reference:
Megan Szymanski, Ruihua Wang, M. Danielle Fallin, Susan S. Bassett, Dimitrios Avramopoulos. Neuroglobin and Alzheimer's dementia: Genetic association and gene expression changes. Neurobiology of Aging, 2008; DOI: 10.1016/j.neurobiolaging.2008.10.003
Adapted from materials provided by Johns Hopkins Medical Institutions.
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Johns Hopkins Medical Institutions (2009, May 8). New Evidence Ties Gene To Alzheimer's. ScienceDaily. Retrieved May 11, 2009, from http://www.sciencedaily.com /releases/2009/05/090506160540.htm
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Friday, April 10, 2009
Rigorous Visual Training Teaches The Brain To See Again After Stroke
ScienceDaily (Apr. 9, 2009) — By doing a set of vigorous visual exercises on a computer every day for several months, patients who had gone partially blind as a result of suffering a stroke were able to regain some vision, according to scientists who published their results in the April 1 issue of the Journal of Neuroscience.
Such rigorous visual retraining is not common for people who suffer blindness after a stroke. That’s in contrast to other consequences of stroke, such as speech or movement difficulties, where rehabilitation is common and successful.
“We were very surprised when we saw the results from our first patients,” said Krystel Huxlin, Ph.D., the neuroscientist and associate professor who led the study of seven patients at the University of Rochester Eye Institute. “This is a type of brain damage that clinicians and scientists have long believed you simply can’t recover from. It’s devastating, and patients are usually sent home to somehow deal with it the best they can.”
The results are a cause for hope for patients with vision damage from stroke or other causes, said Huxlin. The work also shows a remarkable capacity for “plasticity” in damaged, adult brains. It shows that the brain can change a great deal in older adults and that some brain regions are capable of covering for other areas that have been damaged.
Huxlin studied seven people who had suffered a stroke that damaged an area of the brain known as the primary visual cortex or V1, which serves as the gateway to the rest of the brain for all the visual information that comes through our eyes. V1 passes visual information along to dozens of other brain areas, which process and make sense of the information, ultimately allowing us to see.
Patients with damage to the primary visual cortex have severely impaired vision – they typically have a difficult or impossible time reading, driving, or getting out to do ordinary chores like grocery shopping. Patients may walk into walls, oftentimes cannot navigate stores without bumping into goods or other people, and they may be completely unaware of cars on the road coming toward them from the left or right.
Depending on where in the brain the stroke occurred, most patients will be blind in one-quarter to one-half of their normal field of view. Everything right or left of center, depending on the side of the stroke, might be gray or dark, for instance.
Such rigorous visual retraining is not common for people who suffer blindness after a stroke. That’s in contrast to other consequences of stroke, such as speech or movement difficulties, where rehabilitation is common and successful.
“We were very surprised when we saw the results from our first patients,” said Krystel Huxlin, Ph.D., the neuroscientist and associate professor who led the study of seven patients at the University of Rochester Eye Institute. “This is a type of brain damage that clinicians and scientists have long believed you simply can’t recover from. It’s devastating, and patients are usually sent home to somehow deal with it the best they can.”
The results are a cause for hope for patients with vision damage from stroke or other causes, said Huxlin. The work also shows a remarkable capacity for “plasticity” in damaged, adult brains. It shows that the brain can change a great deal in older adults and that some brain regions are capable of covering for other areas that have been damaged.
Huxlin studied seven people who had suffered a stroke that damaged an area of the brain known as the primary visual cortex or V1, which serves as the gateway to the rest of the brain for all the visual information that comes through our eyes. V1 passes visual information along to dozens of other brain areas, which process and make sense of the information, ultimately allowing us to see.
Patients with damage to the primary visual cortex have severely impaired vision – they typically have a difficult or impossible time reading, driving, or getting out to do ordinary chores like grocery shopping. Patients may walk into walls, oftentimes cannot navigate stores without bumping into goods or other people, and they may be completely unaware of cars on the road coming toward them from the left or right.
Depending on where in the brain the stroke occurred, most patients will be blind in one-quarter to one-half of their normal field of view. Everything right or left of center, depending on the side of the stroke, might be gray or dark, for instance.
Neuroscientists Demonstrate The Link Between Brainwave Activity and Visual Perception
ScienceDaily (Apr. 9, 2009) — Can we always see what is in front of us? According to Dr. Tony Ro, a Professor of Psychology and Cognitive Neuroscience at The City College of New York (CCNY), the answer is “no.” New research published in The Journal of Neuroscience by Professor Ro and colleagues from the University of Illinois demonstrates that the brain cannot detect images when brainwave activity is in a trough.
“We may have our eyes open, but we sometimes miss seeing things,” Professor Ro said. “When the brain is in a state of readiness, you see; when it is not, you don’t see.”
Brainwave activity has peaks and troughs that can occur around 10 times a second, he explained. In their research, Professor Ro and his colleagues demonstrated how the phase of the brainwave or alpha wave can reliably predict visual detection.
Subjects were shown a faint image of a dot on a computer screen and asked to indicate whether they saw the image by pushing a button. Subsequently, the dot was masked making it more difficult to see. “We tried to see whether there was variability in people’s ability to see the image,” he said. “When we presented the dots with masks sometimes people saw it and sometimes they didn’t.”
The research has potential applications in improving safety. For example, automobile accidents often occur because drivers miss seeing something, even if for a split second, he explained.
“With brain sensors we might be able to know when people will actually miss seeing something. By being able to predict whether or not someone will see something, we should be able to implement better ways of delivering information to people to ensure that they will detect it. This might then enhance safety, reduce errors, and prevent mishaps that frequently occur because people fail to see something that is right in front of them.”
Professor Ro said future research will investigate what occurs when images are flashed by a strobe light at intervals to match these brainwave frequencies
“We may have our eyes open, but we sometimes miss seeing things,” Professor Ro said. “When the brain is in a state of readiness, you see; when it is not, you don’t see.”
Brainwave activity has peaks and troughs that can occur around 10 times a second, he explained. In their research, Professor Ro and his colleagues demonstrated how the phase of the brainwave or alpha wave can reliably predict visual detection.
Subjects were shown a faint image of a dot on a computer screen and asked to indicate whether they saw the image by pushing a button. Subsequently, the dot was masked making it more difficult to see. “We tried to see whether there was variability in people’s ability to see the image,” he said. “When we presented the dots with masks sometimes people saw it and sometimes they didn’t.”
The research has potential applications in improving safety. For example, automobile accidents often occur because drivers miss seeing something, even if for a split second, he explained.
“With brain sensors we might be able to know when people will actually miss seeing something. By being able to predict whether or not someone will see something, we should be able to implement better ways of delivering information to people to ensure that they will detect it. This might then enhance safety, reduce errors, and prevent mishaps that frequently occur because people fail to see something that is right in front of them.”
Professor Ro said future research will investigate what occurs when images are flashed by a strobe light at intervals to match these brainwave frequencies
Sunday, April 5, 2009
Blood Test For Head Injuries Gains Momentum
Science News
Blood Test For Brain Injuries Gains Momentum
ScienceDaily (Apr. 2, 2009) —
A blood test that can help predict the seriousness of a head injury and detect the status of the blood-brain barrier is a step closer to reality, according to two recently published studies involving University of Rochester Medical Center researchers.
News stories about tragic head injuries – from the death of actress Natasha Richardson to brain-injured Iraq war soldiers and young athletes – certainly underscore the need for a simpler, faster, accurate screening tool, said brain injury expert Jeffrey Bazarian, M.D., M.P.H., associate professor of Emergency Medicine, Neurology and Neurosurgery at URMC, and a co-author on both studies.
The S-100B blood test recently cleared a significant hurdle when a panel of national experts, including Bazarian, agreed for the first time that it could be a useful tool for patients with a mild injury, allowing them to safely avoid a CT scan.
Previous studies have shown the S-100B serum protein biomarker to increase rapidly after an injury. If measured within four hours of the injury, the S-100B test accurately predicts which head injury patients will have a traumatic abnormality such as hemorrhage or skull fracture on a head CT scan. It takes about 20 minutes to get results and could spare many patients unnecessary radiation exposure.
Physicians at six Emergency Departments in upstate New York, including the ED at Strong Memorial Hospital in Rochester, this year will continue to study the accuracy of the test among 1,500 patients. Scientists plan to use the data to apply for U.S. Food and Drug Administration approval.
"The S-100B blood test is an important part of the tool set we need to improve our treatment of patients with brain injuries," Bazarian said. "It's not the ultimate diagnostic test, but it may make things easier for patients, and it will help doctors sort through difficult clinical decisions."
The test is used routinely in 16 European countries as a screening device. If a person falls and gets a head injury in Munich, Germany, during Oktoberfest, for example, a neurosurgeon is on duty within 500 meters of the beer tent, ready to administer the blood test, Bazarian said.
But in the United States, the current, accepted standard screening tool for head injuries is still the CT scan, which shows bleeding in the brain but does not detect more subtle injury to the brain's neurons, which can result in lasting neurological defects. In fact, 95 percent of CT scans look normal for patients with a relatively mild but potentially life-altering injury, Bazarian said.
There are more than 1 million emergency visits annually for traumatic brain injury (TBI) in the U.S. The majority of these visits are for mild injuries, primarily the result of falls and motor vehicle crashes. The challenge for doctors is to identify which of these patients has an acute, traumatic intracranial injury, something that is not always evident, and which patients can be observed and sent home.
Widespread use of the blood test could result in a 30 percent reduction of CT scans, according to the report by the national panel of brain experts, which published updated clinical guidelines in the December 2008 Annals of Emergency Medicine, and the April 2009 Journal of Emergency Nursing.
Bazarian and colleague Brian J. Blyth, M.D., assistant professor of Emergency Medicine at URMC, additionally found that the S-100B test can relay critical information about how the blood-brain barrier (BBB) is functioning after a head injury. Blyth was the first author on this study, reported electronically March 3, 2009, in the Journal of Neurotrauma.
In the context of head injuries, the BBB acts like a gate between the brain tissue and peripheral circulation. The gate often opens after injury, but not always. Knowing the status of the BBB helps doctors to decide if medications given to repair damage will actually reach the brain. The time between injury and irreversible brain swelling is short – and many drug studies have failed to find a therapy that leverages this time frame and works as designed.
Before the S-100B blood test, the best way to know if the BBB was open was to perform an invasive procedure called a ventriculostomy. (Doctors insert a catheter through the skull and into the brain, withdrawal fluid, and compare the concentration of albumin protein in the cerebrospinal fluid to the concentration in the blood.)
In a pilot study of 20 patients, however, Blyth found that serum S-100B concentrations could accurately predict the function of the blood-brain barrier 12 hours after injury, eliminating the need for the invasive procedure.
The study compared levels of S-100B proteins to the CSF-serum albumin quotient (Qa), the gold standard measurement signaling a brain injury. Researchers compared nine people with a known severe head injury, to 11 people who suffered from non-traumatic headaches.
Blyth and Bazarian believe the research may impact future drug studies. "The disability and death rates from brain injuries have not improved much in the past 20 years," Blyth said. "Many clinical trials for new medications have failed, probably because it was difficult to know if the blood-brain barrier was open and the drugs were reaching its target. Our study shows that any diagnostic test for brain injury should incorporate a way to measure the status of the blood-brain barrier into its design."
Blood Test For Brain Injuries Gains Momentum
ScienceDaily (Apr. 2, 2009) —
A blood test that can help predict the seriousness of a head injury and detect the status of the blood-brain barrier is a step closer to reality, according to two recently published studies involving University of Rochester Medical Center researchers.
News stories about tragic head injuries – from the death of actress Natasha Richardson to brain-injured Iraq war soldiers and young athletes – certainly underscore the need for a simpler, faster, accurate screening tool, said brain injury expert Jeffrey Bazarian, M.D., M.P.H., associate professor of Emergency Medicine, Neurology and Neurosurgery at URMC, and a co-author on both studies.
The S-100B blood test recently cleared a significant hurdle when a panel of national experts, including Bazarian, agreed for the first time that it could be a useful tool for patients with a mild injury, allowing them to safely avoid a CT scan.
Previous studies have shown the S-100B serum protein biomarker to increase rapidly after an injury. If measured within four hours of the injury, the S-100B test accurately predicts which head injury patients will have a traumatic abnormality such as hemorrhage or skull fracture on a head CT scan. It takes about 20 minutes to get results and could spare many patients unnecessary radiation exposure.
Physicians at six Emergency Departments in upstate New York, including the ED at Strong Memorial Hospital in Rochester, this year will continue to study the accuracy of the test among 1,500 patients. Scientists plan to use the data to apply for U.S. Food and Drug Administration approval.
"The S-100B blood test is an important part of the tool set we need to improve our treatment of patients with brain injuries," Bazarian said. "It's not the ultimate diagnostic test, but it may make things easier for patients, and it will help doctors sort through difficult clinical decisions."
The test is used routinely in 16 European countries as a screening device. If a person falls and gets a head injury in Munich, Germany, during Oktoberfest, for example, a neurosurgeon is on duty within 500 meters of the beer tent, ready to administer the blood test, Bazarian said.
But in the United States, the current, accepted standard screening tool for head injuries is still the CT scan, which shows bleeding in the brain but does not detect more subtle injury to the brain's neurons, which can result in lasting neurological defects. In fact, 95 percent of CT scans look normal for patients with a relatively mild but potentially life-altering injury, Bazarian said.
There are more than 1 million emergency visits annually for traumatic brain injury (TBI) in the U.S. The majority of these visits are for mild injuries, primarily the result of falls and motor vehicle crashes. The challenge for doctors is to identify which of these patients has an acute, traumatic intracranial injury, something that is not always evident, and which patients can be observed and sent home.
Widespread use of the blood test could result in a 30 percent reduction of CT scans, according to the report by the national panel of brain experts, which published updated clinical guidelines in the December 2008 Annals of Emergency Medicine, and the April 2009 Journal of Emergency Nursing.
Bazarian and colleague Brian J. Blyth, M.D., assistant professor of Emergency Medicine at URMC, additionally found that the S-100B test can relay critical information about how the blood-brain barrier (BBB) is functioning after a head injury. Blyth was the first author on this study, reported electronically March 3, 2009, in the Journal of Neurotrauma.
In the context of head injuries, the BBB acts like a gate between the brain tissue and peripheral circulation. The gate often opens after injury, but not always. Knowing the status of the BBB helps doctors to decide if medications given to repair damage will actually reach the brain. The time between injury and irreversible brain swelling is short – and many drug studies have failed to find a therapy that leverages this time frame and works as designed.
Before the S-100B blood test, the best way to know if the BBB was open was to perform an invasive procedure called a ventriculostomy. (Doctors insert a catheter through the skull and into the brain, withdrawal fluid, and compare the concentration of albumin protein in the cerebrospinal fluid to the concentration in the blood.)
In a pilot study of 20 patients, however, Blyth found that serum S-100B concentrations could accurately predict the function of the blood-brain barrier 12 hours after injury, eliminating the need for the invasive procedure.
The study compared levels of S-100B proteins to the CSF-serum albumin quotient (Qa), the gold standard measurement signaling a brain injury. Researchers compared nine people with a known severe head injury, to 11 people who suffered from non-traumatic headaches.
Blyth and Bazarian believe the research may impact future drug studies. "The disability and death rates from brain injuries have not improved much in the past 20 years," Blyth said. "Many clinical trials for new medications have failed, probably because it was difficult to know if the blood-brain barrier was open and the drugs were reaching its target. Our study shows that any diagnostic test for brain injury should incorporate a way to measure the status of the blood-brain barrier into its design."
Sunday, March 15, 2009
Can Mental Training Games Help Prevent Alzheimer's Disease?
ScienceDaily (Mar. 14, 2009) — Loss of thinking power is a fear shared by many aging baby boomers. That fear has resulted in a budding industry for brain training products – exercises such as Brain Age, Mindfit and My Brain Trainer – which in 2007 generated $80 million in the United States alone.
The premise of brain training is simple: participants must complete a series of daily exercises such as mental calculation, memorization and enigmas to help increase cognitive ability and avoid certain neurodegenerative diseases. Some companies like Brain Center International, which produces NeuroActive, promise regular users they'll shave 10 years of brain aging after eight weeks of use. Is it surprising some 10,000 copies of the product were sold in Quebec in the last six months?
"To my knowledge, there is no scientific research demonstrating results from such recreational programs," says Sylvie Belleville, a professor at the Université de Montréal' Department of Psychology and associate research director of the Institut universitaire de gériatrie de Montréal.
According to Belleville, the principles of intellectual stimulation aren't false, but their efficiency haven't been scientifically proven. She argues that Sudoku and crosswords could work just as well.
Yet there are programs that exist that have been proven to benefit seniors and Alzheimer's victims, according to Belleville: "These programs are based on memory strategies. They have nothing to do with the repetitive exercises offered by NeuroActive and others," she says.
While memory products can be helpful, Belleville warns against the unrealistic expectations some may provide. The advertising of these products, she stresses, "Could give false hopes. If someone doesn't see a change they could quit and it could eventually lead to depression."
In her opinion, the best way to keep one's cerebral functions is to do intellectual activities, eat well, control vascular factors, particularly in the case of diabetes and hypertension, and remain physically active.
The premise of brain training is simple: participants must complete a series of daily exercises such as mental calculation, memorization and enigmas to help increase cognitive ability and avoid certain neurodegenerative diseases. Some companies like Brain Center International, which produces NeuroActive, promise regular users they'll shave 10 years of brain aging after eight weeks of use. Is it surprising some 10,000 copies of the product were sold in Quebec in the last six months?
"To my knowledge, there is no scientific research demonstrating results from such recreational programs," says Sylvie Belleville, a professor at the Université de Montréal' Department of Psychology and associate research director of the Institut universitaire de gériatrie de Montréal.
According to Belleville, the principles of intellectual stimulation aren't false, but their efficiency haven't been scientifically proven. She argues that Sudoku and crosswords could work just as well.
Yet there are programs that exist that have been proven to benefit seniors and Alzheimer's victims, according to Belleville: "These programs are based on memory strategies. They have nothing to do with the repetitive exercises offered by NeuroActive and others," she says.
While memory products can be helpful, Belleville warns against the unrealistic expectations some may provide. The advertising of these products, she stresses, "Could give false hopes. If someone doesn't see a change they could quit and it could eventually lead to depression."
In her opinion, the best way to keep one's cerebral functions is to do intellectual activities, eat well, control vascular factors, particularly in the case of diabetes and hypertension, and remain physically active.
MetabolicAnd Neurological Disorders May Share Common Risk Factors
ScienceDaily (Mar. 15, 2009) — Metabolic disorders such as obesity and diabetes appear to share risk factors with and may influence the development of Alzheimer's disease and other forms of dementia, according to several reports published in the March issue of Archives of Neurology.
The issue—a theme issue on neurological disorders related to metabolic diseases—is being published in conjunction with a JAMA theme issue on diabetes, obesity and their comorbidities.
Studies featured in this issue include the following:
Women With More Components of Metabolic Syndrome More Likely to Develop Cognitive Impairment
Women with the cluster of cardiovascular risk factors known collectively as the metabolic syndrome appear likely to develop cognitive impairment over a four-year period. Kristine Yaffe, M.D., of the University of California, San Francisco, and the San Francisco Veterans' Affairs Medical Center, and colleagues assessed 4,895 older women (average age 66.2) who did not have cognitive impairment at the beginning of the study.
Of the 497 (10.2 percent) women who had the metabolic syndrome 7.2 percent (36) developed cognitive impairment during a four-year period, compared with 4.1 percent (181 of 4,398) of those who did not have the metabolic syndrome. Each additional component of the syndrome—such as abdominal obesity, high blood pressure and low HDL cholesterol levels—was associated with a 23 percent increase in risk of cognitive impairment.
"As the obesity and sedentary lifestyle epidemic escalates throughout the world, identification of the role of these modifiable behaviors in increasing risk for development of deleterious outcomes, such as cognitive impairment, is critical," the authors conclude. "Future research should assess whether identification of cognitive impairment among patients with the metabolic syndrome or more aggressive clinical control of the factors that compose the metabolic syndrome might lessen the risk of developing cognitive impairment in elderly people."
Obesity Associated With Worsening Cognitive Function in Older Men
Older men with higher levels of fat appear more likely to experience declines in cognitive function over seven years, but the same association does not appear to occur in older women. Alka M. Kanaya, M.D., of the University of California–San Francisco, and colleagues studied 3,054 elderly individuals enrolled in the Health ABC Study.
Participants' adiposity (fat level) was assessed by body mass index, waist circumference, sagittal diameter (distance between the back and the highest point of the abdomen), total fat mass and subcutaneous (beneath the skin) and visceral fat (fat between the internal organs) measured by computed tomography. Men whose measurements were higher were more likely to experience declines in scores on a cognitive functioning test administered at the beginning of the study and again after three, five and eight years. However, no association was observed in women.
"Women show trends toward inverse associations, with higher levels of adiposity being associated with less cognitive change," the authors write. "Traditional metabolic factors, adipocytokines [compounds produced by fat tissue] and sex hormones do not explain this sex difference. Future studies should confirm these longitudinal associations with adiposity and cognitive change and investigate why adiposity has inverse associations in men and women."
Obese Middle-Aged Adults and Underweight Older Adults Appear to Have Increased Risk for Dementia
Midlife obesity may be associated with risk for dementia, but after age 65, the relationship between body mass index and dementia appears to reverse so that underweight individuals are at higher risk. Annette L. Fitzpatrick, Ph.D., of the University of Washington, Seattle, and colleagues analyzed data from 2,798 adults (average age 74.7) without dementia. Participants reported their weight at age 50 (midlife) and had their height and weight measured at age 65 or older (late life).
Over an average of 5.4 years of follow-up, 480 individuals developed dementia, including 245 with Alzheimer's disease and 213 with vascular dementia. In evaluations of midlife obesity, individuals with a body mass index (BMI) of higher than 30—classified as obese—were more likely than those of a normal weight to develop dementia. However, those who were underweight (BMI of lower than 20) in late life had an increased risk of dementia, whereas being overweight in late life was not associated with dementia and being obese appeared to have a protective effect.
"The greatest dementia risk was found in underweight individuals at older ages. These findings suggest the predictive ability of BMI changes across time," the authors write. "These results help explain the 'obesity paradox' as differences in dementia risk across time are consistent with physical changes in the trajectory toward disability."
Heart Disease Risk Factors Associated With Faster Cognitive Decline
Individuals with higher total and low-density lipoprotein (LDL, or "bad") cholesterol levels and a history of diabetes appear to experience a more rapid cognitive decline after developing Alzheimer's disease. Elizabeth P. Helzner, Ph.D, and colleagues at the Columbia University Medical Center, New York, studied 156 patients who were diagnosed with Alzheimer's disease at an average age of 83.
During an average of 3.5 years of follow-up, those who had higher LDL and total cholesterol levels before diagnosis experienced a more rapid decline on cognitive test scores than those whose cholesterol levels were in the normal range, as did those with a history of diabetes when compared with those without diabetes.
The study "provides further evidence for the role of vascular risk factors in the course of Alzheimer's disease," the authors conclude. "Prevention or treatment of these conditions can potentially slow the course of Alzheimer's disease."
Review: Insulin Resistance May Links Metabolic and Cognitive Disorders
Insulin resistance, when tissues in the body lose sensitivity to the hormone that regulates glucose, may underlie both dementia and metabolic disorders such as obesity and diabetes. In a review article, Suzanne Craft, Ph.D., of Veterans Administration Puget Sound Health Care System and University of Washington School of Medicine, Seattle, writes that "considerable progress has been made in establishing relationships among metabolic disorders and late-life dementing illnesses," including through the common foundation of insulin resistance.
"A number of challenges must be addressed as we move forward to determine the key mechanisms underlying these associations," Dr. Craft concludes, including establishing clear definitions of both metabolic and neurological conditions. "Future research aimed at identifying mechanisms that underlie comorbid associations will not only provide important insights into the causes and interdependencies of late-life dementias, but will also inspire novel strategies for treating and preventing these disorders."
The issue—a theme issue on neurological disorders related to metabolic diseases—is being published in conjunction with a JAMA theme issue on diabetes, obesity and their comorbidities.
Studies featured in this issue include the following:
Women With More Components of Metabolic Syndrome More Likely to Develop Cognitive Impairment
Women with the cluster of cardiovascular risk factors known collectively as the metabolic syndrome appear likely to develop cognitive impairment over a four-year period. Kristine Yaffe, M.D., of the University of California, San Francisco, and the San Francisco Veterans' Affairs Medical Center, and colleagues assessed 4,895 older women (average age 66.2) who did not have cognitive impairment at the beginning of the study.
Of the 497 (10.2 percent) women who had the metabolic syndrome 7.2 percent (36) developed cognitive impairment during a four-year period, compared with 4.1 percent (181 of 4,398) of those who did not have the metabolic syndrome. Each additional component of the syndrome—such as abdominal obesity, high blood pressure and low HDL cholesterol levels—was associated with a 23 percent increase in risk of cognitive impairment.
"As the obesity and sedentary lifestyle epidemic escalates throughout the world, identification of the role of these modifiable behaviors in increasing risk for development of deleterious outcomes, such as cognitive impairment, is critical," the authors conclude. "Future research should assess whether identification of cognitive impairment among patients with the metabolic syndrome or more aggressive clinical control of the factors that compose the metabolic syndrome might lessen the risk of developing cognitive impairment in elderly people."
Obesity Associated With Worsening Cognitive Function in Older Men
Older men with higher levels of fat appear more likely to experience declines in cognitive function over seven years, but the same association does not appear to occur in older women. Alka M. Kanaya, M.D., of the University of California–San Francisco, and colleagues studied 3,054 elderly individuals enrolled in the Health ABC Study.
Participants' adiposity (fat level) was assessed by body mass index, waist circumference, sagittal diameter (distance between the back and the highest point of the abdomen), total fat mass and subcutaneous (beneath the skin) and visceral fat (fat between the internal organs) measured by computed tomography. Men whose measurements were higher were more likely to experience declines in scores on a cognitive functioning test administered at the beginning of the study and again after three, five and eight years. However, no association was observed in women.
"Women show trends toward inverse associations, with higher levels of adiposity being associated with less cognitive change," the authors write. "Traditional metabolic factors, adipocytokines [compounds produced by fat tissue] and sex hormones do not explain this sex difference. Future studies should confirm these longitudinal associations with adiposity and cognitive change and investigate why adiposity has inverse associations in men and women."
Obese Middle-Aged Adults and Underweight Older Adults Appear to Have Increased Risk for Dementia
Midlife obesity may be associated with risk for dementia, but after age 65, the relationship between body mass index and dementia appears to reverse so that underweight individuals are at higher risk. Annette L. Fitzpatrick, Ph.D., of the University of Washington, Seattle, and colleagues analyzed data from 2,798 adults (average age 74.7) without dementia. Participants reported their weight at age 50 (midlife) and had their height and weight measured at age 65 or older (late life).
Over an average of 5.4 years of follow-up, 480 individuals developed dementia, including 245 with Alzheimer's disease and 213 with vascular dementia. In evaluations of midlife obesity, individuals with a body mass index (BMI) of higher than 30—classified as obese—were more likely than those of a normal weight to develop dementia. However, those who were underweight (BMI of lower than 20) in late life had an increased risk of dementia, whereas being overweight in late life was not associated with dementia and being obese appeared to have a protective effect.
"The greatest dementia risk was found in underweight individuals at older ages. These findings suggest the predictive ability of BMI changes across time," the authors write. "These results help explain the 'obesity paradox' as differences in dementia risk across time are consistent with physical changes in the trajectory toward disability."
Heart Disease Risk Factors Associated With Faster Cognitive Decline
Individuals with higher total and low-density lipoprotein (LDL, or "bad") cholesterol levels and a history of diabetes appear to experience a more rapid cognitive decline after developing Alzheimer's disease. Elizabeth P. Helzner, Ph.D, and colleagues at the Columbia University Medical Center, New York, studied 156 patients who were diagnosed with Alzheimer's disease at an average age of 83.
During an average of 3.5 years of follow-up, those who had higher LDL and total cholesterol levels before diagnosis experienced a more rapid decline on cognitive test scores than those whose cholesterol levels were in the normal range, as did those with a history of diabetes when compared with those without diabetes.
The study "provides further evidence for the role of vascular risk factors in the course of Alzheimer's disease," the authors conclude. "Prevention or treatment of these conditions can potentially slow the course of Alzheimer's disease."
Review: Insulin Resistance May Links Metabolic and Cognitive Disorders
Insulin resistance, when tissues in the body lose sensitivity to the hormone that regulates glucose, may underlie both dementia and metabolic disorders such as obesity and diabetes. In a review article, Suzanne Craft, Ph.D., of Veterans Administration Puget Sound Health Care System and University of Washington School of Medicine, Seattle, writes that "considerable progress has been made in establishing relationships among metabolic disorders and late-life dementing illnesses," including through the common foundation of insulin resistance.
"A number of challenges must be addressed as we move forward to determine the key mechanisms underlying these associations," Dr. Craft concludes, including establishing clear definitions of both metabolic and neurological conditions. "Future research aimed at identifying mechanisms that underlie comorbid associations will not only provide important insights into the causes and interdependencies of late-life dementias, but will also inspire novel strategies for treating and preventing these disorders."
Monday, March 2, 2009
UltrasoundAnd TPA Effective For Stroke
ScienceDaily (Mar. 2, 2009) — An experimental therapy using tiny bubbles activated by transcranial Doppler (TCD) ultrasound combined with the clot busting drug tissue plasminogen activator (tPA) is more effective than tPA alone in treating patients suffering from ischemic stroke, according to new research presented at the American Stroke Association's International Stroke Conference in San Diego.
The findings, presented by Andrei Alexandrov, M.D., director of the UAB (University of Alabama at Birmingham) Comprehensive Stroke Center, and Carlos Molina, M.D., of the Vall d'Hebron Hospital in Barcelona, Spain, show that patients can be treated safely with TCD in combination with a specific dose of the bubbles, called microspheres, and tPA.
The microspheres, developed by ImaRx Therapeutics, are tiny gas-filled lipid structures that cavitate (rapidly expand and collapse) when exposed to ultrasound waves, helping to reopen blocked arteries and restore blood flow.
"These findings demonstrate that ultrasound combined with microspheres and tPA can be tested further in a pivotal clinical trial with the goal of providing a more effective treatment option for stroke patients by promoting faster clearing of blocked blood vessels as well as improved patient outcomes," said Alexandrov, UAB professor of neurology. "It's very promising to see such results, which support the potential of this therapy as a more effective and expansive therapy for stroke patients."
The Phase 1/2 trial involved 35 patients and evaluated two different doses of ImaRx's MRX-801 microspheres. Cohort I and cohort II patients received 1.4 mL and 2.8 mL of microspheres respectively. Control patients received the standard dose of tPA alone.
The researchers report that complete recanalization was achieved in 120 minutes in 67 percent of cohort I patients, in 46 percent of cohort II patients and 33 percent of control patients. Dramatic clinical recovery has achieved in 45 percent of cohort I, 10 percent of cohort II and 27 percent of controls.
In addition, clinical improvement after 90 days was reported in 75 percent of cohort I, 50 percent of cohort II and 36 percent of controls.
According to the American Heart Association, approximately one-third of adults in the United States have some form of cardiovascular disease. Approximately 700,000 adults in the U.S., are afflicted with, and 150,000 die as a result of, some form of stroke each year.
Stroke is the third leading cause of death, and the leading cause of disability, in the United States. The vast majority of strokes are ischemic strokes, meaning that they are caused by blood clots, while the remainder are the more deadly hemorrhagic strokes caused by bleeding in the brain.
The findings, presented by Andrei Alexandrov, M.D., director of the UAB (University of Alabama at Birmingham) Comprehensive Stroke Center, and Carlos Molina, M.D., of the Vall d'Hebron Hospital in Barcelona, Spain, show that patients can be treated safely with TCD in combination with a specific dose of the bubbles, called microspheres, and tPA.
The microspheres, developed by ImaRx Therapeutics, are tiny gas-filled lipid structures that cavitate (rapidly expand and collapse) when exposed to ultrasound waves, helping to reopen blocked arteries and restore blood flow.
"These findings demonstrate that ultrasound combined with microspheres and tPA can be tested further in a pivotal clinical trial with the goal of providing a more effective treatment option for stroke patients by promoting faster clearing of blocked blood vessels as well as improved patient outcomes," said Alexandrov, UAB professor of neurology. "It's very promising to see such results, which support the potential of this therapy as a more effective and expansive therapy for stroke patients."
The Phase 1/2 trial involved 35 patients and evaluated two different doses of ImaRx's MRX-801 microspheres. Cohort I and cohort II patients received 1.4 mL and 2.8 mL of microspheres respectively. Control patients received the standard dose of tPA alone.
The researchers report that complete recanalization was achieved in 120 minutes in 67 percent of cohort I patients, in 46 percent of cohort II patients and 33 percent of control patients. Dramatic clinical recovery has achieved in 45 percent of cohort I, 10 percent of cohort II and 27 percent of controls.
In addition, clinical improvement after 90 days was reported in 75 percent of cohort I, 50 percent of cohort II and 36 percent of controls.
According to the American Heart Association, approximately one-third of adults in the United States have some form of cardiovascular disease. Approximately 700,000 adults in the U.S., are afflicted with, and 150,000 die as a result of, some form of stroke each year.
Stroke is the third leading cause of death, and the leading cause of disability, in the United States. The vast majority of strokes are ischemic strokes, meaning that they are caused by blood clots, while the remainder are the more deadly hemorrhagic strokes caused by bleeding in the brain.
Saturday, February 28, 2009
Alzheimer's-associated Plaques May Impact Throughout the Brain
ScienceDaily (Feb. 27, 2009) — Advanced imaging reveals surprising effects on astrocyte signaling networks. The impact of the amyloid plaques that appear in the brains of patients with Alzheimer's disease may extend beyond the deposits' effects on neurons – the cells that transmit electrochemical signals throughout the nervous system.
In an article in the Feb. 27 issue of Science, researchers from the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND) report that amyloid plaques may also increase the activity of astrocytes, star-shaped nervous system cells traditionally considered to provide a supporting role in normal brain function. They also show that amyloid-induced astrocyte hyperactivity extends throughout the brain rather than being confined to regions directly adjacent to plaques.
"Our work suggests that amyloid plaques might have a more complex role in altering brain function than we had thought," says Kishore Kuchibhotla of MGH-MIND, lead author of the Science article. "Plaques develop rapidly and have been shown to cause relatively acute, localized neuro-toxicity.
We show that astrocytes could provide a network mechanism that may stretch the impact of plaques to more distant areas of the brain."
Astrocytes were long considered to provide passive support to neurons, but in the early 1990s it was discovered in cell culture that they also could transmit signals by means of transient increases in calcium levels that move from cell to cell in a wave-like manner. These calcium waves travel relatively long distances in response to a variety of external stimuli. Since astrocytes are so abundant – making up about half the volume of the brain – and found throughout the brain, the MGH investigators hypothesized that their function may also be affected by the presence of amyloid plaques.
Using cutting-edge imaging techniques that give a real-time view of the activity of brain cells in living mice, the investigators labeled astrocytes with a dye that lights up when a cell is active and shuts off when it is not. They were surprised to see astrocytes flicker on and off at much higher rates in transgenic mice with an abundance of plaques than in plaque-free animals. T
he plaque-associated astrocyte activity appeared to be synchronized and passed to distant areas of the brain in a wave-like fashion. Another imaging technology revealed that resting calcium levels were elevated throughout the astrocyte network of animals with plaques but not in normal mice.
Blocking the activity of neurons did not reduce astrocyte activity, indicating that amyloid's known impact on neuronal activity was not responsible for its apparent effects on astrocytes.
"This is the first clear evidence in a live animal model that amyloid plaques perturb calcium signaling across the astrocyte network via a neuron-independent mechanism," says Kuchibhotla. "It has been suggested that these intercellular calcium waves, which previously had been observed only in response to some sort of external stimulus, indicate the existence of or response to a traumatic insult. Our data support this hypothesis, but whether the calcium signals we observed actually protect or harm cells remains to be determined.
"We've only begun to scratch the surface of how plaque deposition impacts astrocyte function," he adds. "One key question will be how increased astrocyte signaling impacts neuronal function, and another will be whether astrocyte activity limits or intensifies plaque deposition."
Brian Bacskai, PhD, of MGH-MIND, senior author of the Science report, says, "This study not only provides insight into the role of astrocytic networks in the brain, it also suggests new opportunities to manipulate these networks to treat or prevent Alzheimer's disease as well as other neurological disorders. Further studies of pharmacological compounds that interact with astrocytes may someday lead to potential new therapies"
Kuchibhotla is a Harvard University doctoral candidate in Biophysics, working in Bacskai's laboratory. Additional co-authors of the paper are Carli Lattarulo and Bradley Hyman, MD, PhD, both of MGH MIND. The study was supported by grants from the National Institutes of Health.
In an article in the Feb. 27 issue of Science, researchers from the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND) report that amyloid plaques may also increase the activity of astrocytes, star-shaped nervous system cells traditionally considered to provide a supporting role in normal brain function. They also show that amyloid-induced astrocyte hyperactivity extends throughout the brain rather than being confined to regions directly adjacent to plaques.
"Our work suggests that amyloid plaques might have a more complex role in altering brain function than we had thought," says Kishore Kuchibhotla of MGH-MIND, lead author of the Science article. "Plaques develop rapidly and have been shown to cause relatively acute, localized neuro-toxicity.
We show that astrocytes could provide a network mechanism that may stretch the impact of plaques to more distant areas of the brain."
Astrocytes were long considered to provide passive support to neurons, but in the early 1990s it was discovered in cell culture that they also could transmit signals by means of transient increases in calcium levels that move from cell to cell in a wave-like manner. These calcium waves travel relatively long distances in response to a variety of external stimuli. Since astrocytes are so abundant – making up about half the volume of the brain – and found throughout the brain, the MGH investigators hypothesized that their function may also be affected by the presence of amyloid plaques.
Using cutting-edge imaging techniques that give a real-time view of the activity of brain cells in living mice, the investigators labeled astrocytes with a dye that lights up when a cell is active and shuts off when it is not. They were surprised to see astrocytes flicker on and off at much higher rates in transgenic mice with an abundance of plaques than in plaque-free animals. T
he plaque-associated astrocyte activity appeared to be synchronized and passed to distant areas of the brain in a wave-like fashion. Another imaging technology revealed that resting calcium levels were elevated throughout the astrocyte network of animals with plaques but not in normal mice.
Blocking the activity of neurons did not reduce astrocyte activity, indicating that amyloid's known impact on neuronal activity was not responsible for its apparent effects on astrocytes.
"This is the first clear evidence in a live animal model that amyloid plaques perturb calcium signaling across the astrocyte network via a neuron-independent mechanism," says Kuchibhotla. "It has been suggested that these intercellular calcium waves, which previously had been observed only in response to some sort of external stimulus, indicate the existence of or response to a traumatic insult. Our data support this hypothesis, but whether the calcium signals we observed actually protect or harm cells remains to be determined.
"We've only begun to scratch the surface of how plaque deposition impacts astrocyte function," he adds. "One key question will be how increased astrocyte signaling impacts neuronal function, and another will be whether astrocyte activity limits or intensifies plaque deposition."
Brian Bacskai, PhD, of MGH-MIND, senior author of the Science report, says, "This study not only provides insight into the role of astrocytic networks in the brain, it also suggests new opportunities to manipulate these networks to treat or prevent Alzheimer's disease as well as other neurological disorders. Further studies of pharmacological compounds that interact with astrocytes may someday lead to potential new therapies"
Kuchibhotla is a Harvard University doctoral candidate in Biophysics, working in Bacskai's laboratory. Additional co-authors of the paper are Carli Lattarulo and Bradley Hyman, MD, PhD, both of MGH MIND. The study was supported by grants from the National Institutes of Health.
Friday, February 27, 2009
New Research In Alzheimer's Puzzle
ScienceDaily (Feb. 27, 2009) — Yale researchers have filled in a missing gap on the molecular road map of Alzheimer's disease.
In the Feb. 26 issue of the journal Nature, the Yale team reports that cellular prion proteins trigger the process by which amyloid-beta peptides block brain function in Alzheimer's patients.
"It has been a black box," said Stephen M. Strittmatter, senior author of the study and the Vincent Coates Professor of Neurology and director of Cellular Neuroscience, Neurodegeneration and Repair at the Yale School of Medicine. "We have known that amyloid-beta is bad for the brain, but we have not known exactly how amyloid-beta does bad things to neurons."
After an extensive gene expression analysis, the first step in amyloid-beta damage appears to involve cellular prion proteins. These proteins are normally harmless and exist within all cells, but on rare occasions they change shape and cause notorious prion diseases such as Creutzfeldt- Jacob disease, or its well-known variant, mad cow disease.
When the Yale team searched hundreds of thousands of candidates for potential disease-mediating receptors for the specific amyloid-beta form known to play a role in the development of Alzheimer's disease, the most likely candidate was cellular prion proteins. It seems that amyloid-beta peptides latch onto these cellular prion proteins and precipitate the damage in brain cells.
"They start the cascade that make neurons sick" said Strittmatter, a member of the Kavli Institute for Neuroscience.
Since these cellular prion proteins act at an early stage of disease development, the receptors make a promising target for new Alzheimer's therapies, Strittmatter said.
The study does not suggest that the conversion of cellular prion proteins to an infectious agent occurs in Alzheimer's disease, Strittmatter noted. However, the Nature paper does suggest that the role of usually harmless cellular prion proteins in common neurodegenerative diseases should be studied more rigorously, he said.
Other members of the Yale team included Juha Lauren, David A. Gimbel, Haakon B. Nygaard, and John W. Gilbert.
This work was supported by research grants from the Falk Medical Research Trust and the National Institutes of Health.
Adapted from materials provided by Yale University.
In the Feb. 26 issue of the journal Nature, the Yale team reports that cellular prion proteins trigger the process by which amyloid-beta peptides block brain function in Alzheimer's patients.
"It has been a black box," said Stephen M. Strittmatter, senior author of the study and the Vincent Coates Professor of Neurology and director of Cellular Neuroscience, Neurodegeneration and Repair at the Yale School of Medicine. "We have known that amyloid-beta is bad for the brain, but we have not known exactly how amyloid-beta does bad things to neurons."
After an extensive gene expression analysis, the first step in amyloid-beta damage appears to involve cellular prion proteins. These proteins are normally harmless and exist within all cells, but on rare occasions they change shape and cause notorious prion diseases such as Creutzfeldt- Jacob disease, or its well-known variant, mad cow disease.
When the Yale team searched hundreds of thousands of candidates for potential disease-mediating receptors for the specific amyloid-beta form known to play a role in the development of Alzheimer's disease, the most likely candidate was cellular prion proteins. It seems that amyloid-beta peptides latch onto these cellular prion proteins and precipitate the damage in brain cells.
"They start the cascade that make neurons sick" said Strittmatter, a member of the Kavli Institute for Neuroscience.
Since these cellular prion proteins act at an early stage of disease development, the receptors make a promising target for new Alzheimer's therapies, Strittmatter said.
The study does not suggest that the conversion of cellular prion proteins to an infectious agent occurs in Alzheimer's disease, Strittmatter noted. However, the Nature paper does suggest that the role of usually harmless cellular prion proteins in common neurodegenerative diseases should be studied more rigorously, he said.
Other members of the Yale team included Juha Lauren, David A. Gimbel, Haakon B. Nygaard, and John W. Gilbert.
This work was supported by research grants from the Falk Medical Research Trust and the National Institutes of Health.
Adapted from materials provided by Yale University.
Tuesday, February 24, 2009
How We Keep Visual Details In Short-Term Memory
ScienceDaily (Feb. 23, 2009) — Working memory (also known as short term memory) is our ability to keep a small amount of information active in our mind. This is useful for information we need to know on-the-fly, such as a phone number or the few items we need to pick up from the grocery store. We hang on to the information for a brief period of time, just long enough to make a phone call or get through the checkout line, and then we forget it forever.
People voluntarily pick what information they store in short-term memory. Now, using functional magnetic resonance imaging (fMRI), researchers can see just what information people are holding in memory based only on patterns of activity in the brain.
Psychologists from the University of Oregon and the University of California, San Diego, reported their findings in the February issue of Psychological Science. By analyzing blood-flow activity, they were able to identify the specific color or orientation of an object that was intentionally stored by the observer.
The experiments, in which subjects viewed a stimulus for one second and held a specific aspect of the object in mind after the stimulus disappeared, were conducted in the UO's Robert and Beverly Lewis Center for Neuroimaging. In 10-second delays after each exposure, researchers recorded brain activity during memory selection and storage processing in the visual cortex, a brain region that they hypothesized would support the maintenance of visual details in short-term memory.
"Another interesting thing was that if subjects were remembering orientation, then that pattern of activity during the delay period had no information about color, even though they were staring at a colored-oriented stimulus," said Edward Awh, a UO professor of psychology. "Likewise, if they chose to remember color we were able to decode which color they remembered, but orientation information was completely missing."
Researchers used machine-learning algorithms to examine spatial patterns of activation in the early visual cortex that are associated with remembering different stimuli, said John T. Serences, professor of psychology at UC-San Diego. "This algorithm," he said, "can then be used to predict exactly what someone is remembering based on these activation patterns."
Increases in blood flow, as seen with fMRI, are measured in voxels -- small units displayed in a 3-D grid. Different vectors of the grid, corresponding to neurons, respond as subjects view and store their chosen memories. Based on patterns of activity in an individual's visual cortex, located at the rear of the brain, researchers can pinpoint what is being stored and where, Awh said.
The study is similar to one published this month in Nature and led by Vanderbilt University neuroscientist Frank Tong and colleagues, who were able to predict with 80-percent-plus accuracy which patterns individuals held in memory 11 seconds after seeing a stimulus.
"Their paper makes a very similar point to ours," Awh said, "though they did not vary which 'dimension' of the stimulus people chose to remember, and they did not compare the pattern of activity during sensory processing and during memory. They showed that they could look at brain activity to classify which orientation was being stored in memory."
What Awh and colleagues found was that the sensory area of the brain had a pattern of activity that represented only an individual's intentionally stored aspect of the stimulus. This voluntary control in memory selection, Awh said, falls in line with previous research, including that done by Awh and co-author Edward K. Vogel, also of the UO, that there is limited capacity for what can be stored at one time.
People choose what is important and relevant to them, Awh said.
"Basically, our study shows that information about the precise feature a person is remembering is represented in the visual cortex," Serences said, "This is important because it demonstrates that people recruit the same neural machinery during memory as they do when they see a stimulus."
That demonstration, Awh said, supports the sensory recruitment hypothesis, which suggests the same parts of the brain are involved in perception of a stimulus and memory storage.
A fourth co-author with Awh, Serences and Vogel was Edward F. Ester, a UO doctoral student. Serences was with the University of California, Irvine, when the project began. The research was primarily funded by a grant from the National Institutes of Health to Awh, and by support from the UO's Robert and Beverly Lewis Center for Neuroimaging
People voluntarily pick what information they store in short-term memory. Now, using functional magnetic resonance imaging (fMRI), researchers can see just what information people are holding in memory based only on patterns of activity in the brain.
Psychologists from the University of Oregon and the University of California, San Diego, reported their findings in the February issue of Psychological Science. By analyzing blood-flow activity, they were able to identify the specific color or orientation of an object that was intentionally stored by the observer.
The experiments, in which subjects viewed a stimulus for one second and held a specific aspect of the object in mind after the stimulus disappeared, were conducted in the UO's Robert and Beverly Lewis Center for Neuroimaging. In 10-second delays after each exposure, researchers recorded brain activity during memory selection and storage processing in the visual cortex, a brain region that they hypothesized would support the maintenance of visual details in short-term memory.
"Another interesting thing was that if subjects were remembering orientation, then that pattern of activity during the delay period had no information about color, even though they were staring at a colored-oriented stimulus," said Edward Awh, a UO professor of psychology. "Likewise, if they chose to remember color we were able to decode which color they remembered, but orientation information was completely missing."
Researchers used machine-learning algorithms to examine spatial patterns of activation in the early visual cortex that are associated with remembering different stimuli, said John T. Serences, professor of psychology at UC-San Diego. "This algorithm," he said, "can then be used to predict exactly what someone is remembering based on these activation patterns."
Increases in blood flow, as seen with fMRI, are measured in voxels -- small units displayed in a 3-D grid. Different vectors of the grid, corresponding to neurons, respond as subjects view and store their chosen memories. Based on patterns of activity in an individual's visual cortex, located at the rear of the brain, researchers can pinpoint what is being stored and where, Awh said.
The study is similar to one published this month in Nature and led by Vanderbilt University neuroscientist Frank Tong and colleagues, who were able to predict with 80-percent-plus accuracy which patterns individuals held in memory 11 seconds after seeing a stimulus.
"Their paper makes a very similar point to ours," Awh said, "though they did not vary which 'dimension' of the stimulus people chose to remember, and they did not compare the pattern of activity during sensory processing and during memory. They showed that they could look at brain activity to classify which orientation was being stored in memory."
What Awh and colleagues found was that the sensory area of the brain had a pattern of activity that represented only an individual's intentionally stored aspect of the stimulus. This voluntary control in memory selection, Awh said, falls in line with previous research, including that done by Awh and co-author Edward K. Vogel, also of the UO, that there is limited capacity for what can be stored at one time.
People choose what is important and relevant to them, Awh said.
"Basically, our study shows that information about the precise feature a person is remembering is represented in the visual cortex," Serences said, "This is important because it demonstrates that people recruit the same neural machinery during memory as they do when they see a stimulus."
That demonstration, Awh said, supports the sensory recruitment hypothesis, which suggests the same parts of the brain are involved in perception of a stimulus and memory storage.
A fourth co-author with Awh, Serences and Vogel was Edward F. Ester, a UO doctoral student. Serences was with the University of California, Irvine, when the project began. The research was primarily funded by a grant from the National Institutes of Health to Awh, and by support from the UO's Robert and Beverly Lewis Center for Neuroimaging
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