Posts tagged neuroscience
Articles and news from the latest research reports.
A Blueprint for Restoring Touch with a Prosthetic Hand
New research at the University of Chicago is laying the groundwork for touch-sensitive prosthetic limbs that one day could convey real-time sensory information to amputees via a direct interface with the brain.
The research, published early online in the Proceedings of the National Academy of Sciences, marks an important step toward new technology that, if implemented successfully, would increase the dexterity and clinical viability of robotic prosthetic limbs.
“To restore sensory motor function of an arm, you not only have to replace the motor signals that the brain sends to the arm to move it around, but you also have to replace the sensory signals that the arm sends back to the brain,” said the study’s senior author, Sliman Bensmaia, PhD, assistant professor in the Department of Organismal Biology and Anatomy at the University of Chicago. “We think the key is to invoke what we know about how the brain of the intact organism processes sensory information, and then try to reproduce these patterns of neural activity through stimulation of the brain.”
Bensmaia’s research is part of Revolutionizing Prosthetics, a multi-year Defense Advanced Research Projects Agency (DARPA) project that seeks to create a modular, artificial upper limb that will restore natural motor control and sensation in amputees. Managed by the Johns Hopkins University Applied Physics Laboratory, the project has brought together an interdisciplinary team of experts from academic institutions, government agencies and private companies.
Bensmaia and his colleagues at the University of Chicago are working specifically on the sensory aspects of these limbs. In a series of experiments with monkeys, whose sensory systems closely resemble those of humans, they indentified patterns of neural activity that occur during natural object manipulation and then successfully induced these patterns through artificial means.
The first set of experiments focused on contact location, or sensing where the skin has been touched. The animals were trained to identify several patterns of physical contact with their fingers. Researchers then connected electrodes to areas of the brain corresponding to each finger and replaced physical touches with electrical stimuli delivered to the appropriate areas of the brain. The result: The animals responded the same way to artificial stimulation as they did to physical contact.
Next the researchers focused on the sensation of pressure. In this case, they developed an algorithm to generate the appropriate amount of electrical current to elicit a sensation of pressure. Again, the animals’ response was the same whether the stimuli were felt through their fingers or through artificial means.
Finally, Bensmaia and his colleagues studied the sensation of contact events. When the hand first touches or releases an object, it produces a burst of activity in the brain. Again, the researchers established that these bursts of brain activity can be mimicked through electrical stimulation.
The result of these experiments is a set of instructions that can be incorporated into a robotic prosthetic arm to provide sensory feedback to the brain through a neural interface. Bensmaia believes such feedback will bring these devices closer to being tested in human clinical trials.
“The algorithms to decipher motor signals have come quite a long way, where you can now control arms with seven degrees of freedom. It’s very sophisticated. But I think there’s a strong argument to be made that they will not be clinically viable until the sensory feedback is incorporated,” Bensmaia said. “When it is, the functionality of these limbs will increase substantially.”
Chimpanzees communicate with robots
Chimpanzees are willing to socialise with robots, new research reveals. It is the first time that robots have been used to study behaviour in primates other than humans.
The study, by researchers at the University of Portsmouth, shows that chimps respond to even basic movements made by a robot, demonstrating that chimps want to communicate and interact with other ‘creatures’ on a social level. The researchers believe that these basic forms of communication in chimpanzees help to promote greater social bonding and lead to more complex forms of social interaction.
The research, published in Animal Cognition a few days ago, outlines how chimps responded to a human-like robot about the size of a doll. The chimps reacted to small movements made by the robot by inviting play, offering it toys and in one case even laughing at it. They also responded to being imitated by the robot.
The chimps did not appear to be put off by the primitive nature of the gestures but responded in the same way they might to humans or other chimps.
Lead researcher, Dr Marina Davila-Ross, is from the University’s Centre for Comparative and Evolutionary Psychology. She said that the advantage of using a robot in the study was that the chimps could be observed in a controlled but interactive setting while a human researcher was able to examine the chimps’ behaviour without needing to participate. This allowed the researchers to analyse simplest forms of ’social’ interactions.
She said: “It was especially fascinating to see that the chimps recognised when they were being imitated by the robot because imitation helps to promote their social bonding. They showed less active interest when they saw the robot imitate a human.
“Some of the chimps gave the robot toys and other objects and demonstrated an active interest in communicating. This kind of behaviour helps to promote social interactions and friendships. But there were notable differences in how the chimps behaved. Some chimps, for instance, seemed not interested in interacting with the robot and turned away as soon as they saw it.
“In our other studies we have found that humans will also react to robots in ways which suggest a willingness to communicate, even though they know the robots are not real. It’s a demonstration of the basic human desire to communicate and it appears that chimpanzees share this readiness to communicate with others.”
The interactive robot was approximately 45 centimetres high and its head and limbs could move independently while chimpanzee sounds (such as chimpanzee laughter) were sent via a small loudspeaker in its chest area, which was covered by a dress. The chimps first observed a person interacting with the robot which was then turned around to face the chimp while the human researcher looked away to avoid any further communication.
Almost all of the 16 chimpanzees observed showed a level of active communication with the robot, such as gestures and expressions.
Dr Davila-Ross said that the research paves the way for further study using robots to interact with primates and discover more about their social behaviour in a controlled setting, such as how they make friends.
Human Cortical Neurons with interconnecting dendrites, 4,200X by David Scharf.
Cortical Neurons make up the brain’s cortex which in part makes up the cerebral cortex, responsible for memory, attention, perceptual awareness, thought, language, and consciousness.
(Image Credit: BNPS/RPS/David Scharf)
How Exercise Beefs Up the Brain
While our muscles pump iron, our cells pump out something else: molecules that help maintain a healthy brain. But scientists have struggled to account for the well-known mental benefits of exercise, from counteracting depression and aging to fighting Alzheimer’s and Parkinson’s disease. Now, a research team may have finally found a molecular link between a workout and a healthy brain.
Much exercise research focuses on the parts of our body that do the heavy lifting. Muscle cells ramp up production of a protein called FNDC5 during a workout. A fragment of this protein, known as irisin, gets lopped off and released into the bloodstream, where it drives the formation of brown fat cells, thought to protect against diseases such as diabetes and obesity. (White fat cells are traditionally the villains.)
While studying the effects of FNDC5 in muscles, cellular biologist Bruce Spiegelman of Harvard Medical School in Boston happened upon some startling results: Mice that did not produce a so-called co-activator of FNDC5 production, known as PGC-1α, were hyperactive and had tiny holes in certain parts of their brains. Other studies showed that FNDC5 and PGC-1α are present in the brain, not just the muscles, and that both might play a role in the development of neurons.
Spiegelman and his colleagues suspected that FNDC5 (and the irisin created from it) was responsible for exercise-induced benefits to the brain—in particular, increased levels of a crucial protein called brain-derived neurotrophic factor (BDNF), which is essential for maintaining healthy neurons and creating new ones. These functions are crucial to staving off neurological diseases, including Alzheimer’s and Parkinson’s. And the link between exercise and BDNF is widely accepted. “The phenomenon has been established over the course of, easily, the last decade,” says neuroscientist Barbara Hempstead of Weill Cornell Medical College in New York City, who was not involved in the new work. “It’s just, we didn’t understand the mechanism.”
To sort out that mechanism, Spiegelman and his colleagues performed a series of experiments in living mice and cultured mouse brain cells. First, they put mice on a 30-day endurance training regimen. They didn’t have to coerce their subjects, because running is part of a mouse’s natural foraging behavior. “It’s harder to get them to lift weights,” Spiegelman notes. The mice with access to a running wheel ran the equivalent of a 5K every night.
Aside from physical differences between wheel-trained mice and sedentary ones—“they just look a little bit more like a couch potato,” says co-author Christiane Wrann, also of Harvard Medical School, of the latter’s plumper figures—the groups also showed neurological differences. The runners had more FNDC5 in their hippocampus, an area of the brain responsible for learning and memory.
Using mouse brain cells developing in a dish, the group next showed that increasing the levels of the co-activator PGC-1α boosts FNDC5 production, which in turn drives BDNF genes to produce more of the vital neuron-forming BDNF protein. They report these results online today in Cell Metabolism. Spiegelman says it was surprising to find that the molecular process in neurons mirrors what happens in muscles as we exercise. “What was weird is the same pathway is induced in the brain,” he says, “and as you know, with exercise, the brain does not move.”
So how is the brain getting the signal to make BDNF? Some have theorized that neural activity during exercise (as we coordinate our body movements, for example) accounts for changes in the brain. But it’s also possible that factors outside the brain, like those proteins secreted from muscle cells, are the driving force. To test whether irisin created elsewhere in the body can still drive BDNF production in the brain, the group injected a virus into the mouse’s bloodstream that causes the liver to produce and secrete elevated levels of irisin. They saw the same effect as in exercise: increased BDNF levels in the hippocampus. This suggests that irisin could be capable of passing the blood-brain barrier, or that it regulates some other (unknown) molecule that crosses into the brain, Spiegelman says.
Hempstead calls the findings “very exciting,” and believes this research finally begins to explain how exercise relates to BDNF and other so-called neurotrophins that keep the brain healthy. “I think it answers the question that most of us have posed in our own heads for many years.”
The effect of liver-produced irisin on the brain is a “pretty cool and somewhat surprising finding,” says Pontus Boström, a diabetes researcher at the Karolinska Institute in Sweden. But Boström, who was among the first scientists to identify irisin in muscle tissue, says the work doesn’t answer a fundamental question: How much of exercise’s BDNF-promoting effects come from irisin reaching the brain from muscle cells via the bloodstream, and how much are from irisin created in the brain?
Though the authors point out that other important regulator proteins likely play a role in driving BDNF and other brain-nourishing factors, they are focusing on the benefits of irisin and hope to develop an injectable form of FNDC5 as a potential treatment for neurological diseases and to improve brain health with aging.
Scientists shed light on the brain mechanisms behind a debilitating sleep disorder
Researchers at the University of Toronto discover how the body’s muscles accidentally fall asleep while awake
Normally muscles contract in order to support the body, but in a rare condition known as cataplexy the body’s muscles “fall asleep” and become involuntarily paralyzed. Cataplexy is incapacitating because it leaves the affected individual awake, but either fully or partially paralyzed. It is one of the bizarre symptoms of the sleep disorder called narcolepsy.
“Cataplexy is characterized by muscle paralysis during cognitive awareness, but we didn’t understand how this happened until now, said John Peever of the University of Toronto’s Department of Cell & Systems Biology. “We have shown that the neuro-degeneration of the brain cells that synthesize the chemical hypocretin causes the noradrenaline system to malfunction. When the norandrenaline system stops working properly, it fails to keep the motor and cognitive systems coupled. This results in cataplexy – the muscles fall asleep but the brain stays awake.”
Peever and Christian Burgess, also of Cell & Systems Biology used hypocretin-knockout mice (mice that experience cataplexy), to demonstate that a dysfunctional relationship between the noradrenaline system and the hypocretin-producing system is behind cataplexy. The research was recently published in the journal Current Biology.
The scientists first established that mice experienced sudden loss of muscle tone during cataplectic episodes. They then administered drugs to systematically inhibit or activate a particular subset of adrenergic receptors, the targets of noradrenaline. They were able to reduce the incidence of cataplexy by 90 per cent by activating noradrenaline receptors. In contrast, they found that inhibiting the same receptors increased the incidence of cataplexy by 92 per cent. Their next step was to successfully link how these changes affect the brain cells that directly control muscles.
They found that noradrenaline is responsible for keeping the brain cells (motoneurons) and muscles active. But during cataplexy when muscle tone falls, noradrenaline levels disappear. This forces the muscle to relax and causes paralysis during cataplexy. Peever and Burgess found that restoring noradrenaline pre-empted cataplexy, confirming that the noradrenaline system plays a key role.
(Source: media.utoronto.ca)
Two forms of Parkinson’s disease identified
Why can the symptoms of Parkinson’s disease vary so greatly from one patient to another? A consortium of researchers, headed by a team from the Laboratoire CNRS d’Enzymologie et Biochimie Structurales, is well on the way to providing an explanation. Parkinson’s disease is caused by a protein known as alpha-synuclein, which forms aggregates within neurons, killing them eventually. The researchers have succeeded in characterizing and producing two different types of alpha-synuclein aggregates. Better still, they have shown that one of these two forms is much more toxic than the other and has a greater capacity to invade neurons. This discovery takes account, at the molecular scale, of the existence of alpha-synuclein accumulation profiles that differ from one patient to the next. These results, published on October 10 in Nature Communications, represent a notable advance in our understanding of Parkinson’s disease and pave the way for the development of specific therapies targeting each form of the disease.
Parkinson’s disease, which is the second most frequent neurodegenerative disease after Alzheimer’s, affects some 150,000 people in France. According to those suffering from the disease, it can manifest itself in the form of uncontrollable shaking (in 60% of patients) or by less-localized symptoms such as depression, behavioral and motor disorders. These differences in symptoms point to different forms of Parkinson’s disease.
This condition, for which no curative treatment currently exists, is caused by the aggregation in the form of fibrillar deposits of alpha-synuclein, a protein that is naturally abundant at neuron junctions. These misfolded alpha-synuclein aggregates propagate between neurons. When they invade a new neuron, they are capable of recruiting normal alpha-synuclein and adding it to the deposit. For this reason, many researchers advocate that the alpha-synuclein of the aggregates should be considered as an infectious protein, in other words a prion. Highly toxic, the alpha-synuclein deposits end up by triggering a process of apoptosis, i.e. cell death.
The researchers have shown that there is not just one single type of aggregate. They succeeded in producing two types of aggregate that only differ in how the protein stacks up. At the millionth of a millimeter scale, the first form of aggregate resembles spaghetti, whereas the second form is long and flat, recalling the shape of wider pasta such as linguine. The team of scientists then tried to determine whether these structural differences result in functional differences. To find out, they placed the two types of aggregates in contact with neuronal cells in culture. They discovered that the capacity of the “spaghetti” form to bind to and penetrate cells is notably greater than that of the “linguine” form. The “spaghetti” form is also considerably more toxic and rapidly kills the infected cells. This form has shown itself to be capable of resisting the cell mechanisms responsible for eliminating it, whereas the “linguine” form is, to a certain extent, controlled by the cell.
The researchers are convinced that the existence of at least two forms of alpha-synuclein aggregates explains why doctors are faced with different Parkinson’s diseases depending on the patient. Experiments on mice are currently underway to confirm this hypothesis. Furthermore, the scientists consider that analysis of the type of aggregate could lead to an efficient diagnosis method, which would make it possible in particular to assess the virulence of the disease for each patient. Finally, they hope that by refining the characterization of the structure of the aggregates, it will be possible to develop targeted therapeutic strategies for each variant in order to slow down the propagation of abnormal alpha-synuclein within the brain.
New Theory of Synapse Formation in the Brain
The human brain keeps changing throughout a person’s lifetime. New connections are continually created while synapses that are no longer in use degenerate. To date, little is known about the mechanisms behind these processes. Jülich neuroinformatician Dr. Markus Butz has now been able to ascribe the formation of new neural networks in the visual cortex to a simple homeostatic rule that is also the basis of many other self-regulating processes in nature. With this explanation, he and his colleague Dr. Arjen van Ooyen from Amsterdam also provide a new theory on the plasticity of the brain – and a novel approach to understanding learning processes and treating brain injuries and diseases.
The brains of adult humans are by no means hard wired. Scientists have repeatedly established this fact over the last few years using different imaging techniques. This so-called neuroplasticity not only plays a key role in learning processes, it also enables the brain to recover from injuries and compensate for the loss of functions. Researchers only recently found out that even in the adult brain, not only do existing synapses adapt to new circumstances, but new connections are constantly formed and reorganized. However, it was not yet known how these natural rearrangement processes are controlled in the brain. In the open-access journal PLOS Computational Biology, Butz and van Ooyen now present a simple rule that explains how these new networks of neurons are formed.
"It’s very likely that the structural plasticity of the brain is the basis for long-term memory formation," says Markus Butz, who has been working at the recently established Simulation Laboratory Neuroscience at the Jülich Supercomputing Centre for the past few months. "And it’s not just about learning. Following the amputation of extremities, brain injury, the onset of neurodegenerative diseases, and strokes, huge numbers of new synapses are formed in order to adapt the brain to the lasting changes in the patterns of incoming stimuli."
Activity regulates synapse formation
Τhese results show that the formation of new synapses is driven by the tendency of neurons to maintain a ‘pre-set’ electrical activity level. If the average electric activity falls below a certain threshold, the neurons begin to actively build new contact points. These are the basis for new synapses that deliver additional input – the neuron firing rate increases. This also works the other way round: as soon as the activity level exceeds an upper limit, the number of synaptic connections is reduced to prevent any overexcitation – the neuron firing rate falls. Similar forms of homeostasis frequently occur in nature, for example in the regulation of body temperature and blood sugar levels.
However, Markus Butz stresses that this does not work without a certain minimal excitation of the neurons: “A neuron that no longer receives any stimuli loses even more synapses and will die off after some time. We must take this restriction into account if we want the results of our simulations to agree with observations.” Using the visual cortex as an example, the neuroscientists have studied the principles according to which neurons form new connections and abandon existing synapses. In this region of the brain, about 10% of the synapses are continuously regenerated. When the retina is damaged, this percentage increases even further. Using computer simulations, the authors succeeded in reconstructing the reorganization of the neurons in a way that conforms to experimental results from the visual cortex of mice and monkeys with damaged retinas.
The visual cortex is particularly suitable for demonstrating the new growth rule, because it has a property referred to as retinotopy: This means that points projected beside each other onto the retina are also arranged beside each other when they are projected onto the visual cortex, just like on a map. If areas of the retina are damaged, the cells onto which the associated images are projected receive different inputs. “In our simulations, you can see that areas which no longer receive any input from the retina start to build crosslinks, which allow them to receive more signals from their neighbouring cells,” says Markus Butz. These crosslinks are formed slowly from the edge of the damaged area towards the centre, in a process resembling the healing of a wound, until the original activity level is more or less restored.
Synaptic and structural plasticity
"The new growth rule provides structural plasticity with a principle that is almost as simple as that of synaptic plasticity," says co-author Arjen van Ooyen, who has been working on models for the development of neural networks for decades. As early as 1949, psychology professor Donald Olding Hebb discovered that connections between neurons that are frequently activated will become stronger. Those that exchange little information will become weaker. Today, many scientists believe that this Hebbian principle plays a central role in learning and memory processes. While synaptic plasticity in involved primarily in short-term processes that take from a few milliseconds to several hours, structural plasticity extends over longer time scales, from several days to months.
Structural plasticity therefore plays a particularly important part during the (early) rehabilitation phase of patients affected by neurological diseases, which also lasts for weeks and months. The vision driving the project is that valuable ideas for the treatment of stroke patients could result from accurate predictions of synapse formation. If doctors knew how the brain structure of a patient will change and reorganize during treatment, they could determine the ideal times for phases of stimulation and rest, thus improving treatment efficiency.
New approach for numerous applications
"It was previously assumed that structural plasticity also follows the principle of Hebbian plasticity. The findings suggest that structural plasticity is governed by the homeostatic principle instead, which was not taken into consideration before," says Prof. Abigail Morrison, head of the Simulation Laboratory Neuroscience at Jülich. Her team is already integrating the new rule into the freely accessible simulation software NEST, which is used by numerous scientists worldwide.
These findings are also of relevance for the Human Brain Project. Neuroscientists, medical scientists, computer scientists, physicists, and mathematicians in Europe are working hand in hand to simulate the entire human brain on high-performance computers of the next generation in order to better understand how it functions. “Due to the complex synaptic circuitry in the human brain, it’s not plausible that its fault tolerance and flexibility are achieved based on static connection rules. Models are therefore required for a self-organization process,” says Prof. Markus Diesmann from Jülich’s Institute of Neuroscience and Medicine, who is involved in the project. He heads Computational and Systems Neuroscience (INM-6), a subinstitute working at the interface between neuroscientific research and simulation technology.
Scientists identify protein linking exercise to brain health
A protein that is increased by endurance exercise has been isolated and given to non-exercising mice, in which it turned on genes that promote brain health and encourage the growth of new nerves involved in learning and memory, report scientists from Dana-Farber Cancer Institute and Harvard Medical School.
The findings, reported in the journal Cell Metabolism, help explain the well-known capacity of endurance exercise to improve cognitive function, particularly in older people. If the protein can be made in a stable form and developed into a drug, it might lead to improved therapies for cognitive decline in older people and slow the toll of neurodegenerative diseases such Alzheimer’s and Parkinson’s, according to the investigators.
“What is exciting is that a natural substance can be given in the bloodstream that can mimic some of the effects of endurance exercise on the brain,” said Bruce Spiegelman, PhD, of Dana-Farber and HMS. He is co-senior author of the publication with Michael E. Greenberg, PhD, chair of neurobiology at HMS.
The Spiegelman group previously reported that the protein, called FNDC5, is produced by muscular exertion and is released into the bloodstream as a variant called irisin. In the new research, endurance exercise – mice voluntarily running on a wheel for 30 days – increased the activity of a metabolic regulatory molecule, PGC-1α, in muscles, which spurred a rise in FNDC5 protein. The increase of FNDC5 in turn boosted the expression of a brain-health protein, BDNF (brain-derived neurotrophic protein) in the dentate gyrus of the hippocampus, a part of the brain involved in learning and memory.
It has been found that exercise stimulates BDNF in the hippocampus, one of only two areas of the adult brain that can generate new nerve cells. BDNF promotes development of new nerves and synapses – connections between nerves that allow learning and memory to be stored – and helps preserve the survival of brain cells.
How exercise raises BDNF activity in the brain wasn’t known; the new findings linking exercise, PGC-1α, FNDC5 and BDNF provide a molecular pathway for the effect, although Spiegelman and his colleagues suggest there are probably others.
Having shown that FNDC5 is a molecular link between exercise and increased BDNF in the brain, the scientists asked whether artificially increasing FNDC5 in the absence of exercise would have the same effect. They used a harmless virus to deliver the protein to mice through the bloodstream, in hopes the FNDC5 could reach the brain and raise BDNF activity. Seven days later, they examined the mouse brains and observed a significant increase in BDNF in the hippocampus.
“Perhaps the most exciting result overall is that peripheral deliver of FNDC5 with adenoviral vectors is sufficient to induce central expression of Bdnf and other genes with potential neuroprotective functions or those involved in learning and memory,” the authors said. Spiegelman cautioned that further research is needed to determine whether giving FNDC5 actually improves cognitive function in the animals. The scientists also aren’t sure whether the protein that got into the brain is FNDC5 itself, or irisin, or perhaps another variant of the protein.
Spiegelman said that development of irisin as a drug will require creating a more stable form of the protein.
(Source: dana-farber.org)
Researchers find that ‘peanut butter’ test can help diagnose Alzheimer’s disease
A dollop of peanut butter and a ruler can be used to confirm a diagnosis of early stage Alzheimer’s disease, University of Florida Health researchers have found.
Jennifer Stamps, a graduate student in the UF McKnight Brain Institute Center for Smell and Taste, and her colleagues reported the findings of a small pilot study in the Journal of the Neurological Sciences.
Stamps came up with the idea of using peanut butter to test for smell sensitivity while she was working with Dr. Kenneth Heilman, the James E. Rooks distinguished professor of neurology and health psychology in the UF College of Medicine’s department of neurology.
She noticed while shadowing in Heilman’s clinic that patients were not tested for their sense of smell. The ability to smell is associated with the first cranial nerve and is often one of the first things to be affected in cognitive decline. Stamps also had been working in the laboratory of Linda Bartoshuk, the William P. Bushnell presidentially endowed professor in the College of Dentistry’s department of community dentistry and behavioral sciences and director of human research in the Center for Smell and Taste.
“Dr. Heilman said, ‘If you can come up with something quick and inexpensive, we can do it,’” Stamps said.
She thought of peanut butter because, she said, it is a “pure odorant” that is only detected by the olfactory nerve and is easy to access.
In the study, patients who were coming to the clinic for testing also sat down with a clinician, 14 grams of peanut butter — which equals about one tablespoon — and a metric ruler. The patient closed his or her eyes and mouth and blocked one nostril. The clinician opened the peanut butter container and held the ruler next to the open nostril while the patient breathed normally. The clinician then moved the peanut butter up the ruler one centimeter at a time during the patient’s exhale until the person could detect an odor. The distance was recorded and the procedure repeated on the other nostril after a 90-second delay.
The clinicians running the test did not know the patients’ diagnoses, which were not usually confirmed until weeks after the initial clinical testing.
The scientists found that patients in the early stages of Alzheimer’s disease had a dramatic difference in detecting odor between the left and right nostril — the left nostril was impaired and did not detect the smell until it was an average of 10 centimeters closer to the nose than the right nostril had made the detection in patients with Alzheimer’s disease. This was not the case in patients with other kinds of dementia; instead, these patients had either no differences in odor detection between nostrils or the right nostril was worse at detecting odor than the left one.
Of the 24 patients tested who had mild cognitive impairment, which sometimes signals Alzheimer’s disease and sometimes turns out to be something else, about 10 patients showed a left nostril impairment and 14 patients did not. The researchers said more studies must be conducted to fully understand the implications.
“At the moment, we can use this test to confirm diagnosis,” Stamps said. “But we plan to study patients with mild cognitive impairment to see if this test might be used to predict which patients are going to get Alzheimer’s disease.”
Stamps and Heilman point out that this test could be used by clinics that don’t have access to the personnel or equipment to run other, more elaborate tests required for a specific diagnosis, which can lead to targeted treatment. At UF Health, the peanut butter test will be one more tool to add to a full suite of clinical tests for neurological function in patients with memory disorders.
One of the first places in the brain to degenerate in people with Alzheimer’s disease is the front part of the temporal lobe that evolved from the smell system, and this portion of the brain is involved in forming new memories.
“We see people with all kinds of memory disorders,” Heilman said. Many tests to confirm a diagnosis of Alzheimer’s disease or other dementias can be time-consuming, costly or invasive. “This can become an important part of the evaluation process.”
The Cancer Genome Atlas exposes more secrets of lethal brain tumor
Project delves deeply in genomics of 599 glioblastoma multiforme cases to better target disease
When The Cancer Genome Atlas launched its massively collaborative approach to organ-by-organ genomic analysis of cancers, the brain had both the benefit, and the challenge, of going first.
TCGA ganged up on glioblastoma multiforme (GBM), the most common and lethal of brain tumors, with more than 100 scientists from 14 institutions tracking down the genomic abnormalities that drive GBM.
Five years later, older and wiser, TCGA revisited glioblastoma, producing a broader, deeper picture of the drivers – and potential therapeutic targets – of the disease published in the Oct. 10 issue of Cell.
“The first paper in 2008 characterized glioblastoma in important new ways and illuminated the path for all TCGA organ studies that have followed,” said senior author Lynda Chin, M.D., professor and chair of Genomic Medicine and scientific director of the Institute for Applied Cancer Science at The University of Texas MD Anderson Cancer Center.
“Our new study reflects major improvements in technology applied to many more tumor samples to more completely characterize the landscape of genomic alterations in glioblastoma,” said Chin, who was also co-senior author of the first paper while she was on the faculty of Dana-Farber Cancer Institute in Boston.
“Information generated by this unbiased, data-driven analysis presents new opportunities to discover genomics-based biomarkers, understand disease mechanisms and generate new hypotheses to develop better, targeted therapies,” Chin said.
About 23,000 new cases of GBM are predicted in the United States during 2013 and more than 14,000 people expected to die of the disease. Most patients die within 15 months of diagnosis.
Well of rich, detailed data will nurture better treatment
New information about genetic mutations, deletions and amplifications; gene expression and epigenetic regulation; structural changes due to chromosomal alterations, proteomic effects and the molecular networks that drive GBM make for a deep, broad dataset that will underpin research and clinical advances for years to come.
“Our main contribution is this tremendous resource for the GBM research community, which is already heavily relying on the earlier TCGA study,” said co-lead author Roeland Verhaak, Ph.D., assistant professor of Bioinformatics and Computational Biology at MD Anderson. “Whatever new treatments people come up with for GBM, I’m very confident that their discovery and development will in some way have benefited from this rich and detailed data set,” he said.
The Cell paper describes analysis of tumor samples and molecular data from 599 patients at 17 study sites. Detailed clinical information including treatment and survival was available for almost all cases
New targetable mutations
In addition to confirming significantly mutated genes discovered earlier, such as the tumor suppressors TP53, PTEN and RB1 and the oncogene PIK3CA, the analysis identified 61 new mutated genes. The most frequent mutations occurred in from 1.7 to 9 percent of cases.
Two of these, BRAF and FGFR, might have more immediate clinical relevance, Verhaak noted. MD Anderson neuro-oncologists are checking to see if patients have these mutations. Drugs are available to address those variations now, Verhaak said. The BRAF point mutation in GBM is the same commonly found in melanoma, which is treated by a new class of drugs.
More twists and turns for EGFR
The larger data set and an improved analytical algorithm allowed major refinement of gene amplification and deletion information. For example, common amplification events were found to occur more frequently than previously known, including amplification of the epidermal growth factor receptor (EGFR) on chromosome 7.
EGFR is both amplified and mutated frequently in GBM; yet therapeutic efforts targeting EGFR so far have failed. “We found EGFR is more frequently altered than we already thought,” Verhaak said.
Overall, the EGFR gene was mutated, rearranged, amplified or otherwise altered in 57 percent of tumors. Increased EGFR protein levels in GBM cells correlated with the many mechanisms of EGFR alteration, Verhaak said.
A treatment based on EGFR still has great potential, he noted. But strategies to target EGFR will need to address the likelihood that different alterations of EGFR might be present in the same tumor and affect the impact of targeted drugs.
Breaking GBM into molecular subtypes
Verhaak and other researchers in recent years have begun to classify GBM tumors by gene expression. Four such subgroups — neural, proneural, mesenchymal and classical — were further characterized by DNA methylation pattern, signaling pathway activity and by clinical measures such as survival and treatment response. Methylation of a gene turns it off.
Understanding the subgroups could establish biomarkers to guide treatment and identify new therapeutic targets.
The team found, for example, that the survival advantage of the proneural subtype depends on a specific DNA methylation pattern known as G-CIMP and that DNA methylation of the MGMT gene may serve as a biomarker of treatment response in the classical subtype.
(Source: mdanderson.org)