A test to detect brain amyloid deposits associated with Alzheimer disease (AD) provides doctors with useful information on treatment and further testing for patients with cognitive impairment, according to a study published online by the journal Alzheimer Disease & Associated Disorders.
The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.
Positron emission tomography (PET) scans using a biomarker called florbetapir F18 can show amyloid plaques in the brain -- a characteristic feature of AD. "Amyloid imaging results altered physicians' diagnostic thinking, intended testing and management of patients undergoing evaluation for cognitive decline," according to the study by Dr Mark Mintun of Avid Pharmaceuticals, Philadelphia, and colleagues.
Is It Alzheimer Disease? Florbetapir Scan Provides Evidence
The researchers designed a "real-world" study to determine how florbetapir would affect clinical management of patients with cognitive impairment. While a florbetapir PET scan showing amyloid plaques doesn't prove that AD is present, it provides a previously unavailable piece of evidence to support the diagnosis.
The study included 229 patients seen by neurologists or other specialists for evaluation of cognitive decline or impairment of uncertain etiology. Before the florbetapir PET scan, doctors provided a provisional diagnosis, an estimate of their diagnostic confidence, and their plans for further testing and treatment. The goal was to assess the value of florbetapir PET in making the final diagnosis and in providing doctors with useful information for clinical decision making.
The florbetapir PET scans showed amyloid deposits in 113 out of 229 patients. The information provided led doctors to change their diagnosis in 55 percent of cases.
When the provisional diagnosis was AD, imaging results led to a change in diagnosis in 37 percent of cases. When the pre-scan diagnosis was either "indeterminate" or another cause of dementia, the diagnosis changed in over 60 percent of cases. In either direction, the scans increased the physicians' ratings of diagnostic confidence by about 20 percent.
Impact on Treatment and Testing Decisions
Florbetapir PET also provided useful information for treatment decision-making: in 87 percent of patients, the results contributed to at least one change in the treatment plan. The main impact was in deciding whether or not to use medications that are helpful in AD. The scan results also affected decisions on further testing -- in many cases, physicians dropped plans to perform additional brain imaging studies or neuropsychological tests.
Alzheimer disease is the most common cause of dementia, but the diagnosis can be challenging to make. The only definitive way to diagnose AD is by autopsy examination of the brain after death. Up to 20 percent of patients diagnosed with AD turn out not to have had AD on autopsy, while up to 40 percent of patients diagnosed with other causes of dementia have evidence of AD at autopsy.
Florbetapir PET is the first FDA-approved imaging that can estimate amyloid deposits in the brain of a living patient. Previous studies have shown that the scans are accurate in identifying patients later shown to have AD at autopsy.
The new results show that florbetapir PET scans can have a significant effect in "real world" clinical evaluation of patients with cognitive impairment. By strengthening the case for or against a diagnosis of AD, this test can have a significant impact on patient management -- particularly related to the use of AD medications and the need for further testing. Additional studies will be needed to confirm whether "clinical care that includes amyloid imaging will translate into better outcomes" for patients with cognitive impairment and possible AD.
Brief Exercise Immediately Enhances Memory: Results Apply to Older Adults Both With and Without Cognitive Deficits
A short burst of moderate exercise enhances the consolidation of memories in both healthy older adults and those with mild cognitive impairment, scientists with UC Irvine's Center for the Neurobiology of Learning & Memory have discovered.
Most research has focused on the benefits of a long-term exercise program on overall health and cognitive function with age. But the UCI work is the first to examine the immediate effects of a brief bout of exercise on memory.
In their study, post-doctoral researcher Sabrina Segal and neurobiologists Carl Cotman and Lawrence Cahill had people 50 to 85 years old with and without memory deficits view pleasant images -- such as photos of nature and animals -- and then exercise on a stationary bicycle for six minutes at 70 percent of their maximum capacity immediately afterward.
One hour later, the participants were given a surprise recall test on the previously viewed images. Results showed a striking enhancement of memory by exercise in both the healthy and cognitively impaired adults, compared with subjects who did not ride the bike.
"We found that a single, short instance of moderately intense exercise particularly improved memory in individuals with memory deficits," Segal said. "Because of its implications and the need to better understand the mechanism by which exercise may enhance memory, we're following up this study with an investigation of potential underlying biological factors."
She believes the improved memory may be related to the exercise-induced release of norepinephrine, a chemical messenger in the brain known to play a strong role in memory modulation. This hypothesis is based on previous work demonstrating that increasing norepinephrine through pharmacological manipulation sharpens memory and that blocking norepinephrine impairs memory.
In the more recent research, Segal and her colleagues discovered that levels of salivary alpha amylase, a biomarker that reflects norepinephrine activity in the brain, significantly increased in participants after exercise. This correlation was especially strong in people with memory impairment.
"The current findings offer a natural and relatively safe alternative to pharmacological interventions for memory enhancement in healthy older individuals as well as those who suffer from cognitive deficits," Segal noted. "With a growing population of the aged, the need for improvement of quality of life and prevention of mental decline is more important than ever before."
Study results appear in the November issue (Volume 32, Number 4) of the Journal of Alzheimer's Disease. UCI's Alzheimer's Disease Research Center and the National Institute of Mental Health (grant number 575082), a division of the National Institutes of Health, supported the research.
Short snippets of DNA found in tissue provide new insight into human cognitive function and risk for developing certain , according to researchers from the . The findings are published in the November 20th issue of PLoS Biology.
There are nearly 40 million positions in the human genome with DNA sequences that are different than those in non-human primates, making the task of learning which are important and which are inconsequential a challenge for scientists. Rather than comparing these sequences strand by strand, , MD, PhD, Professor of Psychiatry and Neuroscience at Mount Sinai School of Medicine, wanted to identify the crucial set of differences between the two genomes by looking more broadly at the chromatin, the structure that packages the DNA and controls how it is expressed.
They found hundreds of regions throughout the human genome which showed a markedly different chromatin structure in neurons in the prefrontal cortex, a brain region that controls complex emotional and cognitive behavior, compared to non-human primates. The findings of the study provide important insights for diseases that are unique to humans such as Alzheimer’s disease and autism.
“While mapping the human genome has taught us a great deal about human biology, the emerging field of epigenomics may help us identify previously overlooked or discarded sequences that are key to understanding disease,” said Dr. Akbarian. “We identified hundreds of loci that represent untapped areas of study that may have therapeutic potential.”
Dr. Akbarian and his research team isolated small snippets of chromatin fibers from the prefrontal cortex. Next, they analyzed these snippets to determine what genetic signals they were expressing. Many of the sequences with human-specific epigenetic characteristics were, until recently, considered to be “junk DNA” with no particular function.
Now, they present new leads on how the human brain has evolved, and a starting point for studying neurological diseases. For example, the sequence of DPP10—a gene critically important for normal human brain development—not only showed distinct human-specific chromatin structures different from other primate brains such as the chimpanzee or the macaque, but the underlying DNA sequence showed some interesting differences from two extinct primates—the Neanderthal and Denisovan, most closely related to our own species and also referred to as ‘archaic hominins’.
“Many neurological disorders are unique to human and are very hard as a clinical syndrome to study in animals, such as Alzheimer’s disease, autism, and depression,” said Dr. Akbarian. “By studying epigenetics we can learn more about those unique pieces of the human genome.”
The research team also discovered that several of these chromatin regions appear to physically interact with each other inside the cell nucleus, despite being separated by hundreds of thousands of DNA strands on the genome. This phenomenon of “chromatin looping” appears to control the expression of neighboring genes, including several with a critical role for human brain development.
“There is growing consensus among genome researchers that much of what was previously considered as ‘junk sequences’ in our genomes indeed could play some sort of regulatory role,” said Dr. Akbarian.
This study was supported by grants from the National Institutes of Health. Dr. Akbarian plans to do more epigenetic studies in other areas of the brain to see if there are additional chromatin regions that are unique to humans. They also plan to study the epigenomes of other mammals with highly evolved social behaviors such as elephants.
Dr. Akbarian joined in July 2012. He is internationally known for his cutting-edge research on the epigenetic mechanisms of psychiatric disorders. He is a widely recognized expert in advanced chromatin tools—many of which were developed in his laboratory—in conjunction with mouse mutagenesis and behavioral models of mental illness to bridge molecular, cellular, and behavioral investigations. He is also a renowned authority on the epigenetic analysis of human brain tissue examined postmortem.
Prior to joining Mount Sinai, Dr. Akbarian was Director of the Brudnick Neuropsychiatric Research Institute. He received his medical and doctorate degrees from the Freie Universitaet Berlin. Dr. Akbarian completed his postdoctoral training in neuroscience at the University of California at Irvine and the Whitehead Institute, and his residency in psychiatry at Massachusetts General Hospital.
Johns Hopkins researchers report the successful use of a form of MRI to identify what appears to be a key biochemical marker for cognitive impairment in the brains of people with multiple sclerosis (MS). In follow-up experiments on mice with a rodent form of MS, researchers were able to use an experimental compound to manipulate that same marker and dramatically improve learning and memory.
Half of people with MS experience learning and memory problems, for which there is no approved treatment, along with movement abnormalities that characterize the debilitating autoimmune disorder.
"We have a potentially novel treatment for cognitive impairment in MS, a devastating condition on the rise that affects at least 400,000 people in the United States," says study leader Adam I. Kaplin, M.D., Ph.D., an assistant professor of psychiatry and behavioral sciences and neurology at the Johns Hopkins University School of Medicine.
Kaplin cautions that the treatment has so far been used only in mouse models of MS and is years away from clinical trials in people.
Nevertheless, he says, the research, described in the Proceedings of the National Academy of Sciences published online on Nov. 19, has the potential to speed development of new drugs to treat cognitive impairment not only in MS patients, but also in patients with Alzheimer's disease and other neurological conditions.
Along with cognitive difficulties, MS patients can experience numbness, weakness, loss of balance, blurred vision and slurred speech. MS is believed to be caused by the immune system wrongfully attacking a person's own myelin, a fatty protein that insulates nerves and helps them send electrical signals to control movement, speech and other functions.
MRI images of brain lesions can often tell physicians how much damage the disease is doing to the brain, and those findings often correlate with physical disability. But until now, says Kaplin, there has been no way to correlate these image findings with cognitive impairment.
For the study, Kaplin and his colleagues employed magnetic resonance spectroscopy, which uses standard MRI scanners but adds tests to detect and compare various brain chemicals found on the images. The Johns Hopkins team performed the tests on nine occasions on the brains of subjects with MS, focusing on the hippocampus, the brain's learning and memory center, looking at levels of various brain chemicals.
Levels of the neurotransmitter N-acetylaspartylglutamate (NAAG), the most abundant peptide transmitter in the brain, stood out. At the same time patients came in for their MRI scan, they completed eight different cognitive tests. The research team found a strong correlation between levels of NAAG in the right hippocampus and performance on six of the eight cognitive tests. The lower the levels of NAAG, the worse the subjects performed.
Kaplin notes that the availability of stronger MRI magnets in recent years made the NAAG-related findings possible. Buoyed by the strength of the correlation, Kaplin and his team set about determining if the findings were more than incidental.
Kaplin then contacted Barbara S. Slusher, Ph.D., M.A.S., director of the Johns Hopkins Brain Science Institute NeuroTranslational Drug Discovery Program, who has spent years studying NAAG and its metabolism in the brain. Slusher and her colleagues had identified novel drugs that could block the breakdown of NAAG into its component parts by inhibiting the enzyme glutamate carboxypeptidase II (GCPII), including 2-PMPA.
"For years, this has been a treatment in search of a disease," Slusher says.
Teaming up with Kristen A. Rahn, Ph.D., a psychiatry instructor at the Johns Hopkins University School of Medicine, the researchers bred mice with the rodent version of MS and treated them with 2-PMPA.
"Before we could even consider progressing to human trials with this class of drugs, the key was to show that the finding of reduced NAAG in the brains of MS patients was causally related to, and not just correlated with, their cognitive impairment, and to do this we needed to test this out in an animal model of MS," Rahn says.
They found that 2-PMPA was able to increase the NAAG levels in the MS mice close to those of a comparative set of mice without the disease.
Although the mice still showed physical signs of MS, such as dragging limbs and an inability to run quickly, their learning and memory improved significantly.
To test learning and memory, the mice were placed in a maze with one escape hatch but many dead ends. On Day 1, all of the mice wandered around and couldn't find the correct escape hole. By Day 4, healthy mice and mice with MS given 2-PMPA went straight for the hole. They were able to find the hole twice as fast as those mice with MS but no drug.
The mice also were tested for fear conditioning, a marker for memory. On Day 1, a tone was played and then the mice were given a mild shock. Four days later, the researchers found that the healthy control mice and mice with MS given 2-PMPA froze in fear much longer when they heard the tone than other mice with untreated MS, indicating a stronger memory.
Kaplin says that, historically, researchers have considered potential MS drugs to be failures if they didn't alleviate physical symptoms in the animal model. But while 2-PMPA didn't reduce physical disability, it is worth pursuing as a treatment for its "remarkable" ability to improve learning and memory.
Researchers don't know what role NAAG plays in cognition. It is possible, Kaplin says, that simply inhibiting its breakdown and having more of this neurotransmitter improves memory and learning. More studies are needed to elucidate this mechanism.
Kaplin says he hopes that pharmaceutical companies will take a renewed interest in the development of drugs like 2-PMPA for cognition improvement in MS and possibly other neurodegenerative diseases. Because 2-PMPA is not orally active, the researchers are working on new nanotechnology-based delivery systems to get the drug to the brain. In addition, Slusher is collaborating with the pharmaceutical company Eisai Inc. to develop new drugs that could be taken by mouth.
"We are encouraged that there could be a way to enhance cognition in people with MS," Kaplin says. "It's something these patients desperately need."
The study was supported by grants from the National Institutes of Health's National Institute of Mental Health (K23 MH069702 and T32 MH015330), the National Institute of Biomedical Imaging and Bioengineering (P41EB015909), the Montel Williams MS Foundation, the Nancy Davis Foundation for Multiple Sclerosis, the Transverse Myelitis Association and the Johns Hopkins Brain Science Institute.
Other Johns Hopkins researchers involved in this study include Crystal C. Watkins, M.D., Ph.D.; Jesse Alt; Rana Rais, Ph.D.; Marigo Stathis, M.S.; Inna Grishkan; Ciprian M. Crainiceanu, Ph.D.; Martin G. Pomper, M.D., Ph.D.; Camilo Rojas, Ph.D.; Mikhail V. Pletnikov, M.D., Ph.D.; Peter A. Calabresi, M.D.; Jason Brandt, Ph.D.; and Peter B. Barker, D.Phil.
Living in areas of high air pollution can lead to decreased cognitive function in older adults, according to new research presented in San Diego at The Gerontological Society of America's (GSA) 65th Annual Scientific Meeting.
This finding is based on data from the U.S. Environmental Protection Agency and the Health and Retirement Study. The analysis was conducted by Jennifer Ailshire, PhD, a National Institute on Aging postdoctoral fellow in the Center for Biodemography and Population Health and the Andrus Gerontology Center at the University of Southern California.
"As a result of age-related declines in health and functioning, older adults are particularly vulnerable to the hazards of exposure to unhealthy air," Ailshire said. "Air pollution has been linked to increased cardiovascular and respiratory problems, and even premature death, in older populations, and there is emerging evidence that exposure to particulate air pollution may have adverse effects on brain health and functioning as well."
This is the first study to show how exposure to air pollution influences cognitive function in a national sample of older men and women. It suggests that fine air particulate matter - composed of particles that are 2.5 micrometers in diameter and smaller, thought to be sufficiently small that if inhaled they can deposit deep in the lung and possibly the brain - may be an important environmental risk factor for reduced cognitive function.
The study sample included 14,793 white, black, and Hispanic men and women aged 50 and older who participated in the 2004 Health and Retirement Study (a nationally representative survey of older adults). Individual data were linked with data on 2004 annual average levels of fine air particulate matter from the Environmental Protection Agency's Air Quality System monitors across the country. Cognitive function was measured on a scale of 1 to 35 and consisted of tests assessing word recall, knowledge, language, and orientation.
The need for early screening of Alzheimer's Disease and its precursor, Mild Cognitive Impairment, is reaching a critical stage as the world's population ages. Online tools, tests, and tracking products such as Cognitive Labs are a valued resource in the battle to improve cognition. MyBrainTest.org, a research advisory group, reports the following:
Rising Dementia Rates are a Global Health Trend: A positive aspect of rising living standards in most of the world has been a significant improvement in global average life expectancies, increasing from 70 to over 78 years in North America since 1960, while the life expectancy in East Asia & Pacific countries as a group has grown from 47 years to 73 years during this same period.
In tandem with improving life expectancies, the global population of people over age 65 has risen dramatically, from 150 Million in 1960 to over 500 Million in 2010. An important corollary to this trend is the accelerating rate of worldwide dementia cases, which carry significant health care, social, and public policy implications. Over 35 Million people are living with Alzheimer’s and other dementia worldwide today, and this number is projected to increase to 66 Million in 2030 and 115 Million by 2050.
Finding a cure for Alzheimer’s, or a method to significantly need for early detection of Alzheimer’s disease, either in the pre-clinical or Mild Cognitive Impairment (MCI) phase. Companies with active clinical trials include Pfizer, Merck, Eli Lilly, Johnson & Johnson, and Roche-Genentech., continues to be a very challenging goal for stakeholders. A common theme emerging from both completed and ongoing clinical trials is the
An increased research focus on validating methods of testing for Alzheimer’s disease has yielded a number of approaches for detecting disease markers before obvious cognitive impairment symptoms appear. These testing approaches can be broadly segmented into brain imaging tests, neurocognitive tests, cerebrospinal fluid tests, genetic tests, and the future possibility of blood serum tests. Companies providing these testing products include GE Healthcare, Philips, Siemens, Positron Corporation, NeuroTrax, CogState, and others.
To request a free copy of the report “Early Detection Testing for Alzheimer’s Disease”, please go to http://www.mybraintest.org
Why is the polyp Hydra immortal? Researchers from Kiel University decided to study it — and unexpectedly discovered a link to aging in humans.
The study was carried out by the Keil University Medical Center Schleswig-Holstein (UKSH)
The tiny freshwater polyp Hydra does not show any signs of aging and is potentially immortal. There is a rather simple biological explanation for this: these animals exclusively reproduce by budding rather than by mating.
A prerequisite for such vegetative-only reproduction is that each polyp contains stem cells capable of continuous proliferation. Due to its immortality, Hydra has been the subject of many studies regarding aging processes for several years.
When people get older, more and more of their stem cells lose the ability to proliferate and thus to form new cells. Aging tissue cannot regenerate any more, which is why for example muscles decline. Elderly people tend to feel weaker because their heart muscles are affected by this aging process as well.
If it were possible to influence these aging processes, humans could feel physically better for much longer. Studying animal tissue such as those of Hydra — an animal full of active stem cells during all its life — could deliver valuable insight into stem cell aging.
Human longevity gene discovered in Hydra
“Surprisingly, our search for the gene that causes Hydra to be immortal led us to the FoxO gene,“ says Anna-Marei Böhm, PhD student and first author of the study. The FoxO gene exists in all animals and humans and has been known for years. However, until now it was not known why human stem cells become fewer and inactive with increasing age, or which biochemical mechanisms are involved, and whether or not FoxO played a role in aging.
So the research group isolated Hydra’s stem cells and then screened all of their genes. They examined FoxO in several genetically modified polyps: Hydra with normal FoxO, with inactive FoxO, and with enhanced FoxO. The scientists were able to show that animals without FoxO possess significantly fewer stem cells.
Interestingly, the immune system in animals with inactive FoxO also changes drastically. Drastic changes of the immune system similar to those observed in Hydra are also known from elderly humans,“ explains Philip Rosenstiel of the Institute of Clinical Molecular Biology at UKSH, whose research group contributed to the study.
“Our research group demonstrated for the first time that there is a direct link between the FoxO gene and aging,“ says Thomas Bosch from the Zoological Institute of Kiel University, who led the Hydra study. “FoxO has been found to be particularly active in centenarians — people older than one hundred years — which is why we believe that FoxO plays a key role in aging — not only in Hydra but also in humans.“
However, the hypothesis cannot be verified on humans, as this would require a genetic manipulation of humans. Bosch stresses however that the current results are still a big step forward in explaining how humans age. The next step will be to study how the longevity gene FoxO works in Hydra, and how environmental factors influence FoxO activity.
The study has two major conclusions: It confirms that the FoxO gene plays a decisive role in the maintenance of stem cells, and thus determines the life span of animals; and it shows that aging and longevity of organisms depend on two factors: the maintenance of stem cells and the maintenance of a functioning immune system.
The study was funded by the German Research Foundation DFG.
Are Humans becoming less intelligent than previously? This is the assertion of Stanford researcher Gerald Crabtree. Did humans actually become less capable after switching to a more agrarian lifestyle?
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Animals that are socially isolated for prolonged periods make less myelin in the region of the brain responsible for complex emotional and cognitive behavior, researchers at the University at Buffalo and Mt. Sinai School of Medicine report in Nature Neuroscience online.
The research sheds new light on brain plasticity, the brain's ability to adapt to environmental changes. It reveals that neurons aren't the only brain structures that undergo changes in response to an individual's environment and experience, according to one of the paper's lead authors, Karen Dietz, PhD, research scientist in the Department of Pharmacology and Toxicology in the UB School of Medicine and Biomedical Sciences.
Dietz did the work while a postdoctoral researcher at Mt. Sinai School of Medicine; Jia Liu, PhD, a Mt. Sinai postdoctoral researcher, is the other lead author.
The paper notes that changes in the brain's white matter, or myelin, have been seen before in psychiatric disorders, and demyelinating disorders have also had an association with depression. Recently, myelin changes were also seen in very young animals or adolescents responding to environmental changes.
"This research reveals for the first time a role for myelin in adult psychiatric disorders," Dietz says. "It demonstrates that plasticity in the brain is not restricted to neurons, but actively occurs in glial cells, such as the oligodendrocytes, which produce myelin."
Myelin is the crucial fatty material that wraps the axons of neurons and allows them to signal effectively. Normal nerve function is lost in demyelinating disorders, such as MS and the rare, fatal, childhood disease, Krabbe's disease.
This paper reveals that the stress of social isolation disrupts the sequence in which the myelin-making cells, the oligodendrocytes, are formed.
In the experiment, adult mice, normally social animals, were isolated for eight weeks to induce a depressive-like state. They were then introduced to a "novel" mouse, one they hadn't seen before; while mice are normally highly motivated to be social, those who had been socially isolated did not show any interest in interacting with the new mouse, a model of social avoidance and withdrawal.
Brain tissue analysis of the socially isolated animals revealed significantly lower than normal levels of gene transcription for oligodendrocyte cells in the prefrontal cortex, a brain region responsible for emotional and cognitive behavior.
"This research provides the first explanation of the mechanism behind how this brain plasticity occurs," says Dietz, "showing how this change in the level of social interaction of the adult animal resulted in changes in oligodendrocytes."
The key change was that cellular nuclei in the prefrontal cortex contained less heterochromatin, a tightly packed form of DNA material, which is unavailable for gene expression.
"This process of DNA compaction is what signifies that the oligodendrocytes have matured, allowing them to produce normal amounts of myelin," says Dietz. "We have observed in socially isolated animals that there isn't as much compaction, and the oligodendrocytes look more immature. As adults age, normally, you would see more compaction, but when social isolation interferes, there's less compaction and therefore, less myelin being made."
She adds, however, that the research also showed that myelin production went back to normal after a period of social integration, suggesting that environmental intervention was sufficient to reverse the negative consequences of adult social isolation.
The new paper, together with a report published earlier this year by another group showing myelin changes triggered by social isolation early in life will broaden investigations into brain plasticity, says David Dietz, PhD, one of the paper's co-authors, an assistant professor of pharmacology and toxicology at UB.
In addition, adds Karen Dietz, the work has implications for future questions regarding MS and other myelin disorders. "This research suggests that maybe recovery from an MS episode might be enhanced by social interaction," she says. "This opens another avenue of investigation of how mood and myelin disorders may interact with one another." Major funding for the research came from the National Institutes of Health
Scientists at The Scripps Research Institute (TSRI) have identified a new pathway that appears to play a major role in information processing in the brain. Their research also offers insight into how imbalances in this pathway could contribute to cognitive abnormalities in humans.
The study, published in the November 9, 2012 issue of the journal Cell, focuses on the actions of a protein called HDAC4. The researchers found that HDAC4 is critically involved in regulating genes essential for communication between neurons.
"We found that HDAC4 represses these genes, and its function in a given neuron is controlled by activity of other neurons forming a circuit," said TSRI Assistant Professor Anton Maximov, senior investigator for the study.
Searching for Missing Pieces
Synapses, specialized junctions that allow neurons to exchange information, are incredibly complex and built with hundreds of genes. Many of these genes become induced when neurons receive excitatory input from other neurons, including those activated by sensory experiences such as vision, hearing and smell. This process influences the assembly of neural circuits during development, and plays a fundamental role in learning and memory.
The Maximov laboratory is interested in understanding how synapses are formed and regulated. Previous studies have identified several factors necessary for activity-dependent transcription in the brain (transcription is a process of converting genetic information from DNA to RNA), but Maximov notes many puzzles remain to be solved. For example, the majority of synapse-related genes are silent in the embryonic brain, which does not receive direct sensory input from an external world. These genes become de-repressed shortly after birth, yet scientists still know little about the underlying mechanisms of how this happens.
Richard Sando III, a graduate student at the TSRI Kellogg School of Science and Technology, a member of the Maximov lab and the first author of this study, noted the team become interested in class IIa histone deacetylases (HDACs), which include HDAC4, in part because they have been implicated in regulation of transcription of non-neuronal tissues. "Class IIa HDACs are also known to change their cellular localization in response to various signals," he said. "There were hints that, in neurons, the translocation of HDAC4 from the nucleus to cytoplasm may be triggered by synaptic activity. We found that mutant mice lacking excitatory transmitter release in the brain accumulate HDAC4 in neuronal nuclei. But what was really exciting was our discovery that nuclear HDAC4 represses a pool of genes involved in synaptic communication and memory formation."
Coincidentally, Maximov had been familiar with these same genes since his postdoctoral training with Tomas Sudhof, a neuroscientist whose pioneering work resulted in the identification of key elements of the transmitter release machinery. "It was truly astonishing when their names came up in our in vitro genome-wide mRNA profiling screens for neuronal HDAC4 targets," Maximov said.
A Link to a Rare Human Disease
To learn more about the function of HDAC4 in the brain, the team wanted to study its role in a mouse model. First, however, the scientists had to overcome a serious technical obstacle -- HDAC4 also appears to protect neurons from apoptosis (programmed cell death), so complete inactivation of this gene would lead to neurodegeneration. To solve this problem, the team generated mice carrying a mutant form of HDAC4 that could not be exported from the cell nucleus. This mutant repressed transcription independently of neuronal activity.
Another surprise came after the team had already initiated their experiments. Underscoring the team's findings, a human genetic study was published linking mutations in the human HDAC4 locus with a rare form of mental retardation.
"One of these human mutations produces a protein similar to a mutant that we introduced into the mouse brain," said Maximov. "Furthermore, our studies revealed that these mice do not learn and remember as well as normal mice, and their memory loss is associated with deficits in synaptic transmission. The pieces came together."
Most of the work in the new study was performed at TSRI's Dorris Neuroscience Center, which has state-of-the-art imaging, molecular biology and animal facilities. "Here at the DNC we enjoy a terrific research environment," Maximov said. "It would have been very difficult if not impossible for us to successfully perform these studies without the support of Helen Dorris and our senior colleagues who have assembled a highly productive and collaborative group of molecular neuroscientists."
Other contributors to the study, "HDAC4 Governs a Transcriptional Program Essential for Synaptic Plasticity and Memory," were Natalia Gounko and Simon Pieraut from the Maximov Laboratory; John Yates III, professor in the Department of Chemical Physiology at TSRI; and Lujian Liao, a staff scientist in the Yates Laboratory.
The research was funded in part by National Institutes of Health grants MH085776, MH067880-09, RR011823, and NS057096, and by the Novartis Advanced Discovery Institute, The Baxter Foundation and the Helen Dorris Postdoctoral Fellowship.
A model that shows how connections in the brain must change to form memories could help to develop artificial cognitive computers.
Exactly how memories are stored and accessed in the brain is unclear. Neuroscientists, however, do know that a primitive structure buried in the center of the brain, called the hippocampus, is a pivotal region of memory formation. Here, changes in the strengths of connections between neurons, which are called synapses, are the basis for memory formation. Networks of neurons linking up in the hippocampus are likely to encode specific memories.
Since direct tests cannot be performed in the brain, experimental evidence for this process of memory formation is difficult to obtain but mathematical and computational models can provide insight. To this end, Eng Yeow Cheu and co-workers at the A*STAR Institute for Infocomm Research, Singapore, have developed a model that sheds light on the exact synaptic conditions required in memory formation.
Their work builds on a previously proposed model of auto-associative memory, a process whereby a memory is retrieved or completed after partial activation of its constituent neural network. The earlier model proposed that neural networks encoding short-term memories are activated at specific points during oscillations of brain activity. Changes in the strengths of synapses, and therefore the abilities of neurons in the network to activate each other, lead to an auto-associative long-term memory.
Cheu and his team then adapted a mathematical model that describes the activity of a single neuron to incorporate specific characteristics of cells in the hippocampus, including their inhibitory activity. This allowed them to model neural networks in the hippocampus that encode short-term memories. They showed that for successful formation of auto-associative memories, the strength of synapses needs to be within a certain range: if synapses become too strong, the associated neurons are activated at the wrong time and networks become muddled, destroying the memories. If they are not strong enough, however, activation of some neurons in the network is not enough to activate the rest, and memory retrieval fails.
As well as providing insight into how memories may be stored and retrieved in the brain, Cheu thinks this work also has practical applications. "This study has significant implications in the construction of artificial cognitive computers in the future," he says. "It helps with developing artificial cognitive memory, in which memory sequences can be retrieved by the presentation of a partial query." According to Cheu, one can compare it to a single image being used to retrieve a sequence of images from a video clip.
The A*STAR-affiliated researchers contributing to this research are from the Institute for Infocomm Research.
Feelings of malaise, low mood and muddled thinking go hand-in-hand with having a cold and may be due to changes deep inside the brain instead of the cold symptoms themselves, says a study in Brain, Behavior and Immunity.
Research has shown the common cold can affect attention, behavior and cognitive function, even when symptoms aren't present.
Scientists compared mental functioning before and after head colds in 189 men and women from the U.K. When the subjects were healthy, they completed tests assessing reaction time, verbal-reasoning skills, memory and mood. Cold symptoms, such as sore throat and sneezing, were rated on a five-point scale. Sleep duration was assessed.
Of the subjects, 48 developed head colds and were retested when the illness had been present 24 to 96 hours. The 141 who remained healthy were retested after 12 weeks.
There were significant differences between the cold and healthy subjects on measures of mood, including alertness and well-being, reaction time, memory, information processing and speed. Accuracy on memory-recall tests didn't change in either group, though the cold-free subjects improved their test results, indicating that learning may be impaired during a cold, researchers said.
No significant relationships were found between mood changes and nasal secretions, or between performance changes and symptom scores, sleep duration or mood changes.
Read more: http://www.foxnews.com/health/2012/11/09/how-head-cold-will-affect-your-brain/#ixzz2Bkpc7bkg
Retinal implants to help pilots see at night, stimulant drugs to keep surgeons alert and steady handed, cognitive enhancers to focus the minds of executives for a big speech or presentation. Medical and scientific advances are bringing human enhancements into work, but with them, according to a report by British experts, come not only the potential to help society and boost productivity, but also a range of ethical dilemmas.
“We’re not talking science fiction here, we’re talking about advances that could impact significantly on the way we work ... in the near future,” said Genevra Richardson, a professor of law at Kings College London and one of the authors of the report.
The report was published after a joint workshop involving four major British scientific institutions which looked at emerging technologies like cognitive enhancing drugs, bionic limbs and retinal implants that have the potential to change workplaces in the future.
Richardson said that while such developments may benefit society in important ways, such as by boosting workforce productivity, their use also had “significant policy implications” to be considered by governments, employers, workers and trades unions.
“There are a range of technologies in development and in some cases already in use that have the potential to transform our workplaces – for better or for worse,” she said.
Human physical and cognitive enhancements are primarily developed with sick or disabled people in mind, as medicines or therapies to help them overcome mental or physical disorders.
But experts say drugs and other forms of enhancement are being used increasingly by healthy people who want to benefit from the boost they can give to performance.
Barbara Sahakian, a professor of clinical neuropsychology at Cambridge University who contributed to the report, said that Modafinil, a generic drug prescribed for sleep disorders such as narcolepsy, is often used by academics or business leaders traveling to conferences who need to be at the top of their game when delivering a speech.
“They take [sleep] medications on the plane to fall asleep, and take modafinil to wake up when they get there,” she said.
Other stimulants such as Novartis’ Ritalin and Shire’s Adderall, prescribed for conditions like Attention Deficit Hyperactivity Disorder, are also used by healthy people to increase focus.
One issue with this kind of use is the lack of long-term safety studies of such drugs in healthy people, the experts said, so there may be unknown risks ahead. Other problems include whether cognitive enhancers are fair. Is it cheating to go into a job interview or exam having taken a drug to boost your mental focus?
Research from the Massachusetts College of Liberal Arts has estimated that up to 16 percent of students in America also use cognitive enhancers to improve performance in exams or for particular essays or projects.
The report also pointed to visual enhancement technologies, such as retinal implants, that could be used by the military, by night watchmen, safety inspectors or gamekeepers.
Technologies to enhance night vision or extend the range of human vision to include other wavelengths such as ultraviolet light could become a reality relatively soon, it said. Sahakian suggested that for drivers or pilots, such enhancements could reduce fatigue and lower the risk of fatal accidents.
She raised the question of whether employers keen to squeeze more productivity out of a workforce might coerce workers into using enhancements against their will.