Posts tagged science
Articles and news from the latest research reports.
Mutations in VCP gene implicated in a number of neurodegenerative diseases
New research, published in Neuron, gives insight into how single mutations in the VCP gene cause a range of neurological conditions including a form of dementia called Inclusion Body Myopathy, Paget’s Disease of the Bone and Frontotemporal Dementia (IBMPFD), and the motor neuron disease Amyotrophic Lateral Sclerosis (ALS).
Single mutations in one gene rarely cause such different diseases. This study shows that these mutations disrupt energy production in cells shedding new light on the role of VCP in these multiple disorders.
In healthy cells VCP helps remove damaged mitochondria, the energy-producing engines of cells. The mutant protein can’t do this and as a result, the dysfunctional mitochondria build up.
The new study led by Dr Fernando Bartolome, Dr Helene Plun-Favreau and Dr Andrey Abramov of the UCL Institute of Neurology, found that mitochondria are damaged in cells from patients with mutant VCP. Mitochondria generate a cell’s energy, and the study found these damaged mitochondria are less efficient, burning more nutrients but producing less energy. This reduction in available energy makes cells more vulnerable, which could explain why mutations in the VCP gene lead to neurological disorders.
Lead author Dr Fernando Bartolome said, “We have found that VCP mutations are associated with mitochondrial dysfunction. VCP had previously been shown to be important in the removal of damaged mitochondria and proteins, accumulation of which is potentially very toxic to cells. A single mutation in the VCP gene could cause multiple neurological diseases because a different type of protein is accumulating in each disorder”.
In the study, the researchers used live imaging techniques to examine the functioning of mitochondria in patient cells carrying three independent VCP mutations, and in nerve cells in which the amount of VCP has been reduced.
“The next step will be to find small molecules able to correct the mitochondrial dysfunction in the VCP deficient cells”, added Dr Bartolome .
Dr Brian Dickie, the Motor Neuron Disease Association’s Director of Research Development says: “Neurons - and motor neurons in particular - are incredibly energy hungry cells. These new findings from the team at UCL show that there is a significant interruption of energy supply in this hereditary form of MND, which has strong implications for understanding the degenerative process underpinning all forms of the disease.”
Sleepwalkers sometimes remember what they’ve done
Three myths about sleepwalking – sleepwalkers have no memory of their actions, sleepwalkers’ behaviour is without motivation, and sleepwalking has no daytime impact – are dispelled in a recent study led by Antonio Zadra of the University of Montreal and its affiliated Sacré-Coeur Hospital. Working from numerous studies over the last 15 years at the hospital’s Centre for Advanced Studies in Sleep Medicine at the Hôpital du Sacré-Cœur de Montréal and a thorough analysis of the literature, Zadra and his colleagues have raised the veil on sleepwalking and clarified the diagnostic criteria for researchers and clinicians. Their findings were published in Lancet Neurology.
Question: What are the causes and consequences of sleepwalking?
A.Z.: “Several indicators suggest that a genetic factor is involved. In 80% of sleepwalkers, a family history of sleepwalking exists. The concordance of sleepwalking is five times higher in monozygotic twins compared to non-identical twins. Our studies have also shown that lack of sleep and stress can lead to sleepwalking. Any situation that disrupts sleep can result in sleepwalking episodes in predisposed individuals.”
A.Z.: “Most sleepwalking episodes are harmless. Apart from the fact that the deep slow-wave sleep of sleepwalkers is fragmented, wanderings are usually brief and pose no danger, or when they do, it is minimal. In rare cases, wandering episodes may be longer, and sleepwalkers may injure themselves and put themselves or others in danger: some have even gone as far as driving a car!”
Question: It is said that the sleep disorder mainly affects children. Is this true?
A.Z.: “Many children transitionally sleepwalk between 6 and 12 years of age. It is thought that passing from sleep to wakefulness requires a certain maturation of the brain. In some children, the brain may have difficulty making this transition. Often, the problem disappears after puberty. But sleepwalking may persist into adulthood in almost 25% of cases. It decreases with age, however, because the older you get, the fewer hours of deep slow-wave sleep you enjoy, which is the stage in which sleepwalking episodes occur.”
A.Z.: “Both children and adults are in a state of so-called dissociated arousal during wandering episodes: parts of the brain are asleep while others are awake. There are elements of wakefulness since sleepwalkers can perform actions such as washing, opening and closing doors, or going down stairs. Their eyes are open and they can recognize people. But there are also elements specific to sleep: sleepwalkers’ judgment and their ability for self-thought are altered, and their behavioural reactions are nonsensical.”
Question: According to you, the idea that people are partially awake and partially asleep is something that must be considered in conceptualizing sleepwalking?
A.Z.: “Absolutely. This is one of the points we outline in our article. There are increasing signs that even in normal subjects the brain does not fall asleep in a single block all at once. Sleep may occur in a localized manner. Parts of the brain can fall asleep before others.”
Question: This may explain why the amnesia of sleepwalkers is not always complete. But can sleepwalkers really remember their actions while sleeping vertically?
A.Z.: “Yes. In children and adolescents, amnesia is more frequent, probably due to neurophysiological reasons. In adults, a high proportion of sleepwalkers occasionally remember what they did during their sleepwalking episodes. Some even remember what they were thinking and the emotions they felt.”
Question: Your work has also shown that the behaviour of sleepwalkers is not simply automatic. Can you explain?
A.Z.: “This is another popular myth. There is a misconception that sleepwalkers do things without knowing why. However, there is a significant proportion of sleepwalkers who remember what they have done and can explain the reasons for their actions. They are the first to say, once awake, that their explanations are nonsensical. However, during the episode, there is an underlying rationale. For example, a man once took his dog that had been sleeping at the foot of his bed to the bathtub to douse it with water. He thought his dog was on fire! There was neither the logic nor the judgment typical of wakefulness. But the behaviour was not automatic in the sense that a motivation accompanied and explained the action.”
Question: Another myth you are interested in relates to impact on the waking state. According to you, beyond the nocturnal phenomenon, sleepwalking is associated with diurnal disorders characterized by somnolence.
A.Z.: “Around 45% of sleepwalkers are clinically somnolent during the day. Younger sleepwalkers are able to hide it more easily. Compared to control subjects, however, they perform less well in vigilance tests. And if given the opportunity to take a nap, they fall asleep faster than normal subjects do.”
A.Z.: “Over the last few years, we have shown that the deep slow-wave sleep of sleepwalkers is atypical. Fragmented by numerous micro-arousals of 3 to 10 seconds, their sleep is less restorative. Sleepwalking is therefore not only a problem of transitioning between deep sleep and wakefulness. There is something more fundamental in their sleep every night, whether or not they have sleepwalking episodes.”
New Early Warning System for the Brain Development of Babies
A new research technique, pioneered by Dr. Maria Angela Franceschini, was published in JoVE (Journal of Visualized Experiments) on March 14th. Researchers at Massachusetts General Hospital and Harvard Medical School have developed a non-invasive optical measurement system to monitor neonatal brain activity via cerebral metabolism and blood flow.
Of the nearly four million children born in the United States each year, 12% are born preterm, 8% are born with low birth weight, and 1-2% of infants are at risk for death associated with respiratory distress. The result is an average infant mortality rate of 6 deaths per 1,000 live births. These statistics, though low compared to those of 50 or even 20 years ago, are troubling both to parents and to clinicians. Until recently there were no effective bedside methods to screen for brain injury or monitor injury progression that can contribute to developmental abnormalities or infant mortality. Dr. Franceschini’s new system does both.
“We want to measure cerebral vascular development and brain health in babies,” Dr. Franceschini tells us. Because neuronal metabolism is hard to measure directly, scientists instead evaluate cerebral oxygen metabolism, which highly corresponds to neuronal metabolism. Dr. Franceschini and her team have developed a near infrared optical system to quantify cerebral oxygen metabolism by measuring blood oxygen saturation and blood flow.
The technology is an improvement on continuous-wave near-infrared spectroscopy (CWNIRS), which measures oxygen saturation but does not provide long-term or real time brain monitoring. Instead, frequency-domain near-infrared spectroscopy (FDNIRS) is used in conjunction with diffuse correlation spectroscopy (DCS) to get a more robust evaluation of infant health. Dr. Franceschini explains, “CWNIRS has been used for many years but it only provides relative measurements of blood oxygen saturation. Our technology allows quantification of multiple vascular parameters and evaluation of oxygen metabolism which gives a more direct picture of infant distress.”
“This technology will let us monitor babies who may be having seizures, cerebral hemorrhages, or other cerebral distresses and may allow us to expedite treatment,” says Dr. Franceschini, who plans to develop and streamline this technology to one that nurses can use clinically. “We chose to publish in JoVE because it is important to show how these measurements can be done and this publication lets us reach early adopters.”
Researchers Show that Suppressing the Brain’s “Filter” Can Improve Performance in Creative Tasks
The brain’s prefrontal cortex is thought to be the seat of cognitive control, working as a kind of filter that keeps irrelevant thoughts, perceptions and memories from interfering with a task at hand.
Now, researchers at the University of Pennsylvania have shown that inhibiting this filter can boost performance for tasks in which unfiltered, creative thoughts present an advantage.
The research was conducted by Sharon Thompson-Schill, the Christopher H. Browne Distinguished Professor of Psychology and director of the Center for Cognitive Neuroscience, and Evangelia Chrysikou, a member of her lab who is now an assistant professor at the University of Kansas. They collaborated with Roy Hamilton and H. Branch Coslett of the Department of Neurology at Penn’s Perelman School of Medicine and Abhishek Datta and Marom Bikson of the Department of Biomedical Engineering at the City College of New York.
Their work was published in the journal Cognitive Neuroscience.
Transplanted brain cells in monkeys light up personalized therapy
For the first time, scientists have transplanted neural cells derived from a monkey’s skin into its brain and watched the cells develop into several types of mature brain cells, according to the authors of a new study in Cell Reports. After six months, the cells looked entirely normal, and were only detectable because they initially were tagged with a fluorescent protein.
Because the cells were derived from adult cells in each monkey’s skin, the experiment is a proof-of-principle for the concept of personalized medicine, where treatments are designed for each individual.
And since the skin cells were not “foreign” tissue, there were no signs of immune rejection — potentially a major problem with cell transplants. “When you look at the brain, you cannot tell that it is a graft,” says senior author Su-Chun Zhang, a professor of neuroscience at the University of Wisconsin-Madison. “Structurally the host brain looks like a normal brain; the graft can only be seen under the fluorescent microscope.”
Marina Emborg, an associate professor of medical physics at UW-Madison and the lead co-author of the study, says, “This is the first time I saw, in a nonhuman primate, that the transplanted cells were so well integrated, with such a minimal reaction. And after six months, to see no scar, that was the best part.”
The cells were implanted in the monkeys “using a state-of-the-art surgical procedure” guided by an MRI image, says Emborg. The three rhesus monkeys used in the study at the Wisconsin National Primate Research Center had a lesion in a brain region that causes the movement disorder Parkinson’s disease, which afflicts up to 1 million Americans. Parkinson’s is caused by the death of a small number of neurons that make dopamine, a signaling chemical used in the brain.
The transplanted cells came from induced pluripotent stem cells (iPS cells), which can, like embryonic stem cells, develop into virtually any cell in the body. iPS cells, however, derive from adult cells rather than embryos.
In the lab, the iPS cells were converted into neural progenitor cells. These intermediate-stage cells can further specialize into the neurons that carry nerve signals, and the glial cells that perform many support and nutritional functions. This final stage of maturation occurred inside the monkey.
Zhang, who was the first in the world to derive neural cells from embryonic stem cells and then iPS cells, says one key to success was precise control over the development process. “We differentiate the stem cells only into neural cells. It would not work to transplant a cell population contaminated by non-neural cells.”
Another positive sign was the absence of any signs of cancer, says Zhang — a worrisome potential outcome of stem cell transplants. “Their appearance is normal, and we also used antibodies that mark cells that are dividing rapidly, as cancer cells are, and we do not see that. And when you look at what the cells have become, they become neurons with long axons [conducting fibers], as we’d expect. They also produce oligodendrocytes that are helping build insulating myelin sheaths for neurons, as they should. That means they have matured correctly, and are not cancerous.”
The experiment was designed as a proof of principle, says Zhang, who leads a group pioneering the use of iPS cells at the Waisman Center on the UW-Madison campus. The researchers did not transplant enough neurons to replace the dopamine-making cells in the brain, and the animal’s behavior did not improve.
Although promising, the transplant technique is a long way from the clinic, Zhang adds. “Unfortunately, this technique cannot be used to help patients until a number of questions are answered: Can this transplant improve the symptoms? Is it safe? Six months is not long enough… And what are the side effects? You may improve some symptoms, but if that leads to something else, then you have not solved the problem.”
Nonetheless, the new study represents a real step forward that may benefit human patients suffering from several diseases, says Emborg. “By taking cells from the animal and returning them in a new form to the same animal, this is a first step toward personalized medicine.”
The need for treatment is incessant, says Emborg, noting that each year, Parkinson’s is diagnosed in 60,000 patients. “I’m gratified that the Parkinson’s Disease Foundation took a risk as the primary funder for this small study. Now we want to move ahead and see if this leads to a real treatment for this awful disease.”
"It’s really the first-ever transplant of iPS cells from a non-human primate back into the same animal, not just in the brain," says Zhang. "I have not seen anybody transplanting reprogrammed iPS cells into the blood, the pancreas or anywhere else, into the same primate. This proof-of-principle study in primates presents hopes for personalized regenerative medicine."
(Source: news.wisc.edu)
Pig brain models provide insights into human cognitive development
A mutual curiosity about patterns of growth and development in pig brains has brought two University of Illinois research groups together. Animal scientists Rod Johnson and Ryan Dilger have developed a model of the pig brain that they plan to use to answer important questions about human brain development.
“It is important to characterize the normal brain growth trajectory from the neonatal period to sexual maturity,” said Johnson.
“Until we know how the brain grows, we don’t know what is going to change,” added Dilger.
In cooperation with the Beckman Institute, they performed MRI scans on the brains of 16 piglets, starting at the age of 2 weeks, then at 4 weeks, and then at 4-week intervals up to 24 weeks.
“We have world-class people at the Beckman Institute who are pushing and developing the next generation of neuroimaging technology, so we’re able to connect with them and take advantage of their expertise,” said Johnson.
Matt Conrad, a student in Johnson’s lab, used three-dimensional visualization software on over 200 images to manually segment each region on three planes. The software put the information together into a three-dimensional image of the pig brain. This is used to determine the volume of the different structures.
When the piglets were at Beckman for their imaging sessions, Dilger performed other tests, including diffusion tensor imaging (DTI), which shows how neural tracks develop, allowing the exploration of brain complexity and of how neurons form. It was also possible to measure neurochemicals, including creatine and acetylcholine, in the brain, which provides a unique insight into brain metabolism.
The end result of this work is what they call the deformable pig brain atlas.
“We are taking 16 pigs and averaging them, so it’s more representative of all pigs,” said Dilger. “You can then apply it to any individual pig to see how it’s different.”
“It’s called a deformable brain atlas because the software takes information from an individual and deforms it until it fits the template, and then you know how much it had to be deformed to fit,” Johnson explained. “So from that, you can tell whether a brain region is larger or smaller compared to the average.”
Johnson and Dilger said that the goal is to develop a tool for pigs that is equivalent to what is available for the mouse brain and make it publicly available. But they don’t want to stop with tool development.
“We want to use this to address important questions,” Johnson said.
One research direction being pursued in Johnson’s lab is to induce viral pneumonia in piglets at the point in the post-natal period when the brain is undergoing massive growth to see how it alters brain growth and development. They are also looking at effects of prenatal infections in the mother to see if that alters the trajectory of normal brain growth in the offspring. The risk for behavioral disorders and reduced stress resilience is increased by pre- and post-natal infection, but the developmental origins are poorly understood.
Dilger’s group is interested in the effects of early-life nutrition on the brain. They are looking at the effects of specific fatty acids as primary structural components of the human brain and cerebral cortex, and at choline, a nutrient that is important for DNA production and normal functioning of neurons.
“Choline deficiency has been tied to cognitive deficits in the mouse and human, and we’re developing a pig model to study the direct effects choline deficiency has on brain structure and function,” Dilger said. “Many women of child-bearing age may not be receiving enough choline in their diets, and recent evidence suggests this may ultimately affect learning and memory ability in their children. Luckily, choline can be found in common foods, especially eggs and meat products, including bacon.”
Normal prion protein regulates iron metabolism
An iron imbalance caused by prion proteins collecting in the brain is a likely cause of cell death in Creutzfeldt-Jakob disease (CJD), researchers at Case Western Reserve University School of Medicine have found.
The breakthrough follows discoveries that certain proteins found in the brains of Alzheimer’s and Parkinson’s patients also regulate iron. The results suggest that neurotoxicity by the form of iron, called redox-active iron, may be a trait of neurodegenerative conditions in all three diseases, the researchers say.
Further, the role of the normal prion protein known as PrPc in iron metabolism may provide a target for strategies to maintain iron balance and reduce iron-induced neurotoxicity in patients suffering from CJD, a rare degenerative disease for which no cure yet exists.
The researchers report that lack of PrPC hampers iron uptake and storage and more findings are now in the online edition of the Journal of Alzheimer’s Disease.
"There are many skeptics who think iron is a bystander or end-product of neuronal death and has no role to play in neurodegenerative conditions," said Neena Singh, a professor of pathology and neurology at Case Western Reserve and the paper’s senior author. "We’re not saying that iron imbalance is the only cause, but failure to maintain stable levels of iron in the brain appears to contribute significantly to neuronal death."
Prions are misfolded forms of PrPC that are infectious and disease-causing agents of CJD. PrPc is the normal form present in all tissues including the brain. PrPc acts as a ferrireductase, that is, it helps to convert oxidized iron to a form that can be taken up and utilized by the cells, the scientists show.
In their investigation, mouse models that lacked PrPC were iron-deficient. By supplementing their diets with excess inorganic iron, normal levels of iron in the body were restored. When the supplements stopped, the mice returned to being iron-deficient.
Examination of iron metabolism pathways showed that the lack of PrPC impaired iron uptake and storage, and alternate mechanisms of iron uptake failed to compensate for the deficiency.
Cells have a tight regulatory system for iron uptake, storage and release. PrPC is an essential element in this process, and its aggregation in CJD possibly results in an environment of iron imbalance that is damaging to neuronal cells, Singh explained
It is likely that as CJD progresses and PrPC forms insoluble aggregates, loss of ferrireductase function combined with sequestration of iron in prion aggregates leads to insufficiency of iron in diseased brains, creating a potentially toxic environment, as reported earlier by this group and featured in Nature Journal club.
Recently, members of the Singh research team also helped to identify a highly accurate test to confirm the presence of CJD in living sufferers. They found that iron imbalance in the brain is reflected as a specific change in the levels of iron-management proteins other than PrPc in the cerebrospinal fluid. The fluid can be tapped to diagnose the disease with 88.9 percent accuracy, the researchers reported in the journal Antioxidants & Redox Signaling online last month.
Singh’ s team is now investigating how prion protein functions to convert oxidized iron to a usable form. They are also evaluating the role of prion protein in brain iron metabolism, and whether the iron imbalance observed in cases of CJD, Alzheimer’s disease and Parkinson’s disease is reflected in the cerebrospinal fluid. A specific change in the fluid could provide a disease-specific diagnostic test for these disorders.
(Source: eurekalert.org)
New MRI method fingerprints tissues and diseases
A new method of magnetic resonance imaging (MRI) could routinely spot specific cancers, multiple sclerosis, heart disease and other maladies early, when they’re most treatable, researchers at Case Western Reserve University and University Hospitals (UH) Case Medical Center suggest in the journal Nature.
Each body tissue and disease has a unique fingerprint that can be used to quickly diagnose problems, the scientists say.
By using new MRI technologies to scan for different physical properties simultaneously, the team differentiated white matter from gray matter from cerebrospinal fluid in the brain in about 12 seconds, with the promise of doing this much faster in the near future.
The technology has the potential to make an MRI scan standard procedure in annual check-ups, the authors believe. A full-body scan lasting just minutes would provide far more information and require no radiologist to interpret the data, making diagnostics cheap, compared to today’s scans, they contend.
"The overall goal is to specifically identify individual tissues and diseases, to hopefully see things and quantify things before they become a problem," said Mark Griswold, a radiology professor at Case Western Reserve School of Medicine and UH Case Medical Center. "But to try to get there, we’ve had to give up everything we knew about the MRI and start over."
Griswold has been working on this goal with Case Western Reserve’s Vikas Gulani, MD, an assistant professor of radiology, and Nicole Seiberlich, assistant professor of biomedical engineering, for a decade. During the last three years, they developed the technology and proved the concept with graduate student Dan Ma; Kecheng Liu, PhD, collaborations manager from Siemens Medical Solutions Inc.; Jeffrey L. Sunshine, MD, professor of radiology and a radiologist at UH Case Medical Center; and Jeffrey L. Duerk, dean of Case School of Engineering and professor of biomedical engineering.
(Image: Rex Features)
Neuron Loss in Schizophrenia and Depression Could Be Prevented With an Antioxidant
Gamma-aminobutyric acid (GABA) deficits have been implicated in schizophrenia and depression. In schizophrenia, deficits have been particularly well-described for a subtype of GABA neuron, the parvalbumin fast-spiking interneurons. The activity of these neurons is critical for proper cognitive and emotional functioning.
It now appears that parvalbumin neurons are particularly vulnerable to oxidative stress, a factor that may emerge commonly in development, particularly in the context of psychiatric disorders like schizophrenia or bipolar disorder, where compromised mitochondrial function plays a role. parvalbumin neurons may be protected from this effect by N-acetylcysteine, also known as Mucomyst, a medication commonly prescribed to protect the liver against the toxic effects of acetaminophen (Tylenol) overdose, reports a new study in the current issue of Biological Psychiatry.
Dr. Kim Do and collaborators, from the Center for Psychiatric Neurosciences of Lausanne University in Switzerland, have worked many years on the hypothesis that one of the causes of schizophrenia is related to vulnerability genes/factors leading to oxidative stress. These oxidative stresses can be due to infections, inflammations, traumas or psychosocial stress occurring during typical brain development, meaning that at-risk subjects are particularly exposed during childhood and adolescence, but not once they reach adulthood.
Their study was performed with mice deficient in glutathione, a molecule essential for cellular protection against oxidations, leaving their neurons more exposed to the deleterious effects of oxidative stress. Under those conditions, they found that the parvalbumin neurons were impaired in the brains of mice that were stressed when they were young. These impairments persisted through their life. Interestingly, the same stresses applied to adults had no effect on their parvalbumin neurons.
Most strikingly, mice treated with the antioxidant N-acetylcysteine, from before birth and onwards, were fully protected against these negative consequences on parvalbumin neurons.
“These data highlight the need to develop novel therapeutic approaches based on antioxidant compounds such as N-acetylcysteine, which could be used preventively in young at-risk subjects,” said Do. “To give an antioxidant from childhood on to carriers of a genetic vulnerability for schizophrenia could reduce the risk of emergence of the disease.”
“This study raises the possibility that GABA neuronal deficits in psychiatric disorder may be preventable using a drug, N-acetylcysteine, which is quite safe to administer to humans,” added Dr. John Krystal, Editor of Biological Psychiatry.
(Source: elsevier.com)
Enhancing Cognition with Video Games: A Multiple Game Training Study
Background
Previous evidence points to a causal link between playing action video games and enhanced cognition and perception. However, benefits of playing other video games are under-investigated. We examined whether playing non-action games also improves cognition. Hence, we compared transfer effects of an action and other non-action types that required different cognitive demands.
Methodology/Principal Findings
We instructed 5 groups of non-gamer participants to play one game each on a mobile device (iPhone/iPod Touch) for one hour a day/five days a week over four weeks (20 hours). Games included action, spatial memory, match-3, hidden- object, and an agent-based life simulation. Participants performed four behavioral tasks before and after video game training to assess for transfer effects. Tasks included an attentional blink task, a spatial memory and visual search dual task, a visual filter memory task to assess for multiple object tracking and cognitive control, as well as a complex verbal span task. Action game playing eliminated attentional blink and improved cognitive control and multiple-object tracking. Match-3, spatial memory and hidden object games improved visual search performance while the latter two also improved spatial working memory. Complex verbal span improved after match-3 and action game training.
Conclusion/Significance
Cognitive improvements were not limited to action game training alone and different games enhanced different aspects of cognition. We conclude that training specific cognitive abilities frequently in a video game improves performance in tasks that share common underlying demands. Overall, these results suggest that many video game-related cognitive improvements may not be due to training of general broad cognitive systems such as executive attentional control, but instead due to frequent utilization of specific cognitive processes during game play. Thus, many video game training related improvements to cognition may be attributed to near-transfer effects.