Posts tagged brain damage
Articles and news from the latest research reports.
Study Suggests Low Vitamin D Causes Damage to Brain
A new study led by University of Kentucky researchers suggests that a diet low in vitamin D causes damage to the brain.
In addition to being essential for maintaining bone health, newer evidence shows that vitamin D serves important roles in other organs and tissue, including the brain. Published in Free Radical Biology and Medicine, the UK study showed that middle-aged rats that were fed a diet low in vitamin D for several months developed free radical damage to the brain, and many different brain proteins were damaged as identified by redox proteomics. These rats also showed a significant decrease in cognitive performance on tests of learning and memory.
"Given that vitamin D deficiency is especially widespread among the elderly, we investigated how during aging from middle-age to old-age how low vitamin D affected the oxidative status of the brain," said lead author on the paper Allan Butterfield, professor in the UK Department of Chemistry, director of the Center of Membrane Sciences, faculty of Sanders-Brown Center on Aging, and director of the Free Radical Biology in Cancer Core of the Markey Cancer Center. “Adequate vitamin D serum levels are necessary to prevent free radical damage in brain and subsequent deleterious consequences."
Previously, low levels of vitamin D have been associated with Alzheimer’s disease, and it’s also been linked to the development of certain cancers and heart disease. In both the developed world and in areas of economic hardship where food intake is not always the most nutritious, vitamin D levels in humans are often low, particularly in the elderly population. Butterfield recommends persons consult their physicians to have their vitamin D levels determined, and if low that they eat foods rich in vitamin D, take vitamin D supplements, and/or get at least 10-15 minutes of sun exposure each day to ensure that vitamin D levels are normalized and remain so to help protect the brain.
(Source: uknow.uky.edu)
Blood Test Accurately Diagnoses Concussion and Predicts Long Term Cognitive Disability
A new blood biomarker correctly predicted which concussion victims went on to have white matter tract structural damage and persistent cognitive dysfunction following a mild traumatic brain injury (mTBI). Researchers in the Perelman School of Medicine at the University of Pennsylvania, in conjunction with colleagues at Baylor College of Medicine, found that the blood levels of a protein called calpain-cleaved αII-spectrin N-terminal fragment (SNTF) were twice as high in a subset of patients following a traumatic injury. If validated in larger studies, this blood test could identify concussion patients at increased risk for persistent cognitive dysfunction or further brain damage and disability if returning to sports or military activities.
More than 1.5 million children and adults suffer concussions each year in the United States, and hundreds of thousands of military personal endure these mild traumatic brain injuries worldwide. Current tests are not capable of determining the extent of the injury or whether the injured person will be among the 15-30 percent who experience significant, persistent cognitive deficits, such as processing speed, working memory and the ability to switch or balance multiple thoughts.
"New tests that are fast, simple, and reliable are badly needed to predict who may experience long-term effects from concussions, and as new treatments are developed in the future, to identify who should be eligible for clinical trials or early interventions," said lead author Robert Siman, PhD, research professor of Neurosurgery at Penn. "Measuring the blood levels of SNTF on the day of a brain injury may help to identify the subset of concussed patients who are at risk of persistent disability."
In a study published yesterday in Frontiers in Neurology, Penn and Baylor researchers evaluated blood samples and diffusion tensor images from a subgroup of 38 participants in a larger study of mTBI with ages ranging from 15 to 25 years old. 17 had sustained a head injury caused by blunt trauma, acceleration or deceleration forces, 13 had an orthopaedic injury, and 8 were healthy, uninjured, demographically matched controls.
In taking neuropsychological and cognitive tests over the course of three months, results within the mTBI group varied considerably, with some patients performing as well as the healthy controls throughout, while others showed impairment initially that resolved by three months, and a third group with cognitive dysfunction persisting through three months. The nine patients who had abnormally high levels of SNTF (7 mTBI and 2 orthopaedic patients) also had significant white matter damage apparent in radiological imaging.
"The blood test identified SNTF in some of the orthopaedic injury patients as well, suggesting that these injuries could also lead to abnormalities in the brain, such as a concussion, that may have been overlooked with existing tests," said Douglas Smith, MD, director of the Penn Center for Brain Injury and Repair and professor of Neurosurgery. "SNTF as a marker is consistent with our earlier research showing that calcium is dumped into neurons following a traumatic brain injury, as SNTF is a marker for neurodegeneration driven by calcium overload."
The blood test given on the day of the mild traumatic brain injury showed 100 percent sensitivity to predict concussions leading to persisting cognitive problems, and 75 percent specificity to correctly rule out those without functionally harmful concussions. If validated in larger studies, a blood test measuring levels of SNTF could be helpful in diagnosing and predicting risk of long term consequences of concussion. The Penn and Baylor researchers hope to determine the robustness of these findings with a second larger study, and determine the best time after concussion to measure SNTF in the blood in order to predict persistent brain dysfunction. The team also wants to evaluate their blood test for identifying when repetitive concussions begin to cause brain damage and persistent disability.
(Source: uphs.upenn.edu)
Surgeons Find New Method to Reduce Risk of Blood Clots During Brain Traumas
Researchers from the University of Missouri School of Medicine have found that a new protocol that uses preventive blood-thinning medication in the treatment of patients with traumatic brain injuries reduces the risk of patients developing life-threatening blood clots without increasing the risk of bleeding inside the brain.
According to the Centers for Disease Control and Prevention, at least 1.7 million traumatic brain injuries occur each year. One of the most common complications associated with traumatic brain injuries is the risk of dangerous blood clots that can form in the circulatory system elsewhere in the body. For patients with traumatic injuries, the body forms blood clots which can break loose and travel to the lungs or other areas, causing dangerous complications.
"Our study found that treating traumatic brain-injured patients with an anticoagulant, or blood-thinning medication, is safe and decreases the risk of these dangerous clots," said N. Scott Litofsky, MD, chief of the MU School of Medicine’s Division of Neurological Surgery and director of neuro-oncology and radiosurgery at MU Health Care. "We found that patients treated with preventive blood thinners had a decreased risk of deep-vein blood clots and no increased risk of intracranial hemorrhaging."
In May 2009, Litofsky, along with study co-author Stephen Barnes, MD, acute care surgeon and chief of the MU Division of Acute Care Surgery, created a new protocol for treating head trauma patients in University Hospital’s Frank L. Mitchell Jr., M.D., Trauma Center using blood-thinning medications.
"One of the main challenges in treating patients with traumatic brain injuries is balancing the risk of intracranial bleeding with the risk of blood clots formed elsewhere in the body," Litofsky said.
In the study, the researchers compared the outcomes of 107 patients with traumatic brain injuries who were treated before the new protocol was put into place with the outcomes of 129 patients who were treated with the blood-thinning medication. Among the patients who did not receive blood thinners, six experienced deep-venous clotting, compared with zero instances of the condition in patients who received the medication. Among the patients who did not receive blood thinners, three patients experienced increased bleeding in the brain, compared with one patient who received the medication.
"Based on our results, we will continue to follow the new protocol in our trauma center, and we believe that other trauma centers would benefit from adopting a similar protocol in their practice," Litofsky said. "If we look at this issue across the country, we should hopefully see this complication occurring less often in brain-injured patients."
The study, “Safety and Efficacy of Early Thromboembolism Chemoprophylaxis After Intracranial Hemorrhage from Traumatic Brain Injury,” was published online Sept. 20 by the Journal of Neurosurgery, the journal for the American Association of Neurological Surgeons.
(Source: medicine.missouri.edu)
Biosensor Could Help Detect Brain Injuries During Heart Surgery
Johns Hopkins engineers and cardiology experts have teamed up to develop a fingernail-sized biosensor that could alert doctors when serious brain injury occurs during heart surgery. By doing so, the device could help doctors devise new ways to minimize brain damage or begin treatment more quickly.
In the Nov. 11 issue of the journal Chemical Science, the team reported on lab tests demonstrating that the prototype sensor had successfully detected a protein associated with brain injuries.
“Ideally, the testing would happen while the surgery is going on, by placing just a drop of the patient’s blood on the sensor, which could activate a sound, light or numeric display if the protein is present,” said the study’s senior author, Howard E. Katz, a Whiting School of Engineering expert in organic thin film transistors, which form the basis of the biosensor.
The project originated about two years ago when Katz, who chairs the Department of Materials Science and Engineering, was contacted by Allen D. Everett, a Johns Hopkins Children’s Center pediatric cardiologist who studies biomarkers linked to pulmonary hypertension and brain injury. As brain injury can occur with heart surgery in both adults and children, the biosensor Everett proposed should work on patients of all ages. He is particularly concerned, however, about operating room injuries to children, whose brains are still developing.
“Many of our young patients need one or more heart surgeries to correct congenital heart defects, and the first of these procedures often occurs at birth,” Everett said. “We take care of these children through adulthood, and we have all have seen the neurodevelopment problems that occur as a consequence of their surgery and post-operative care. These are very sick children, and we have done a brilliant job of improving overall survival from congenital heart surgery, but we have far to go to improve the long-term outcomes of our patients. This is our biggest challenge for the 21st century.”
He said that recent studies found that after heart surgery, about 40 percent of infant patients will have brain abnormalities that show up in MRI scans. The damage is most often caused by strokes, which can be triggered and made worse by multiple events during surgery and recovery, when the brain is most susceptible to injury. These brain injuries can lead to deficiencies in the child’s mental development and motor skills, as well as hyperactivity and speech delay.
To address these problems, Everett sought an engineer to design a biosensor that responds to glial fibrillary acidic protein (GFAP), which is a biomarker linked to brain injuries. “If we can be alerted when the injury is occurring,” he said, “then we should be able to develop better therapies. We could improve our control of blood pressure or redesign our cardiopulmonary bypass machines. We could learn how to optimize cooling and rewarming procedures and have a benchmark for developing and testing new protective medications.”
At present, Everett said, doctors have to wait years for some brain injury-related symptoms to appear. That slows down the process of finding out whether new procedures or treatments to reduce brain injuries are effective. The new device may change that. “The sensor platform is very rapid,” Everett said. “It’s practically instantaneous.”
To create this sensor, materials scientist Katz turned to an organic thin film transistor design. In recent years sensors built on such platforms have shown that they can detect gases and chemicals associated with explosives. These transistors were an attractive choice for Everett’s request because of their potential low cost, low power consumption, biocompatibility and their ability to detect a variety of biomolecules in real time. Futhermore, the architecture of these transistors could accommodate a wide variety of other useful electronic materials.
The sensing area is a small square, 3/8ths-of-an-inch on each side. On the surface of the sensor is a layer of antibodies that attract GFAP, the target protein. When this occurs, it changes the physics of other material layers within the sensor, altering the amount of electrical current that is passing through the device. These electrical changes can be monitored, enabling the user to know when GFAP is present.
“This sensor proved to be extremely sensitive,” Katz said. “It recognized GFAP even when there were many other protein molecules nearby. As far as we’ve been able to determine, this is the most sensitive protein detector based on organic thin film transistors.”
Through the Johns Hopkins Technology Transfer Office, the team members have filed for full patent protection for the new biosensor. Katz said the team is looking for industry collaborators to conduct further research and development of the device, which has not yet been tested on human patients. But with the right level of effort and support, Katz believes the device could be put into clinical use within five years. “I’m getting tremendous personal satisfaction from working on a major medical project that could help patients,” he said.
Everett, the pediatric cardiologist, said the biosensor could eventually be used outside of the operating room to quickly detect brain injuries among athletes and accident victims. “It could evolve into a point-of-care or point-of-injury device,” he said. “It might also be very useful in hospital emergency departments to screen patients for brain injuries.”
(Source: releases.jhu.edu)
![Researcher Seeks to Help Those Who Can’t Speak for Themselves
When people appear comatose, how can we know their wishes?
A Michigan Technological University researcher says many non-communicative individuals may actually be able to express themselves better than is widely thought.
Syd Johnson, assistant professor of philosophy, has just published a paper in the American Journal of Bioethics: Neuroscience that argues that even patients with severe brain injuries could have more self-determination and empowerment. “New research with people using just their brains to communicate reveals that more of them might be able to make their own decisions,” she says.
Those decisions can literally be life and death, and the first question a caregiver should ask is “How do we determine if they are capable—as an ordinary person would be—of making these decisions?” Johnson asks.
She says because of their brain injuries, many have limited attention spans or movement/speech disorders that make it very difficult to communicate. “That’s why it’s important to find ways of assessing their wellbeing other than by asking them,” she says. “Being able to do that would open up the possibility of assessing quality of life even in those who have never been able to communicate, such as infants or people born with severe cognitive disabilities.”
And that leads to the tough questions, Johnson points out.
“Who makes the decision that someone desires, or not, to live in this state? Who makes the life assessment for people: to treat them or to allow them to die.”
The range of potential patients runs the gamut from grandparents to infants, Johnson says. Sometimes you can’t ask them, including those with cognitive disabilities, but sometimes you can.
She acknowledges the complexity of the issue, especially when decisions involve quality of life. “We assume they don’t want to live that way, but sometimes, are they okay?”
She uses the example of locked-in syndrome, where patients can blink “yes” or “no.” A majority says they are doing okay.
“So, then do we make a decision based on what we think it is like to be in that position?” Johnson says.
Many people adjust to this new way of life, she says, and it’s important for caregivers to get into their mind, to recognize what might be a foreign viewpoint for an able-bodied person.
“Then there are the misdiagnosed,” Johnson says. “As many as 40 percent could be conscious at some level, even in a permanent vegetative state. Even in a nursing home, it can be that no one is assessing them, and they might improve. Nobody is diagnosing anymore, and they are treated as if they are not ever going to get better.”
Researchers around the globe have begun to address these issues, and new evidence is coming in, thanks in part to fMRI: functional magnetic resonance imaging—a technique that directly measures the blood flow in the brain that can provide information on brain activity.
“Even EEGs [electroencephalograms, which measure electrical activity in the brain] can be used,” she says. “The patients can be asked questions and given two things to think about for answers: playing tennis for yes, walking around in their house for no. And different parts of their brain will light up. People can be conscious while appearing outwardly unconscious.”
The end-result could mean reassessing the quality of life, Johnson says. Some patients can be asked—the so-called “covertly aware” patients who are conscious but can communicate only with technological assistance.
“Just as importantly, we might be able to use technology to objectively measure aspects of quality of life even in patients who cannot communicate at all,” Johnson says.
The ethical issues loom.
“A person’s quality of life is inherently subjective, and the aim of quality of life assessment has always been to find ways to objectively measure that subjective state of being,” she says. “New technologies like fMRI might be able to provide a different kind of objective assessment of subjective wellbeing—by looking at brain activity—in those individuals who are unable to tell us how they’re doing.”](http://40.media.tumblr.com/ce0e8428706a17904c2f68ea5825b39a/tumblr_mvxwqpuv7I1rog5d1o1_500.jpg)
Researcher Seeks to Help Those Who Can’t Speak for Themselves
When people appear comatose, how can we know their wishes?
A Michigan Technological University researcher says many non-communicative individuals may actually be able to express themselves better than is widely thought.
Syd Johnson, assistant professor of philosophy, has just published a paper in the American Journal of Bioethics: Neuroscience that argues that even patients with severe brain injuries could have more self-determination and empowerment. “New research with people using just their brains to communicate reveals that more of them might be able to make their own decisions,” she says.
Those decisions can literally be life and death, and the first question a caregiver should ask is “How do we determine if they are capable—as an ordinary person would be—of making these decisions?” Johnson asks.
She says because of their brain injuries, many have limited attention spans or movement/speech disorders that make it very difficult to communicate. “That’s why it’s important to find ways of assessing their wellbeing other than by asking them,” she says. “Being able to do that would open up the possibility of assessing quality of life even in those who have never been able to communicate, such as infants or people born with severe cognitive disabilities.”
And that leads to the tough questions, Johnson points out.
“Who makes the decision that someone desires, or not, to live in this state? Who makes the life assessment for people: to treat them or to allow them to die.”
The range of potential patients runs the gamut from grandparents to infants, Johnson says. Sometimes you can’t ask them, including those with cognitive disabilities, but sometimes you can.
She acknowledges the complexity of the issue, especially when decisions involve quality of life. “We assume they don’t want to live that way, but sometimes, are they okay?”
She uses the example of locked-in syndrome, where patients can blink “yes” or “no.” A majority says they are doing okay.
“So, then do we make a decision based on what we think it is like to be in that position?” Johnson says.
Many people adjust to this new way of life, she says, and it’s important for caregivers to get into their mind, to recognize what might be a foreign viewpoint for an able-bodied person.
“Then there are the misdiagnosed,” Johnson says. “As many as 40 percent could be conscious at some level, even in a permanent vegetative state. Even in a nursing home, it can be that no one is assessing them, and they might improve. Nobody is diagnosing anymore, and they are treated as if they are not ever going to get better.”
Researchers around the globe have begun to address these issues, and new evidence is coming in, thanks in part to fMRI: functional magnetic resonance imaging—a technique that directly measures the blood flow in the brain that can provide information on brain activity.
“Even EEGs [electroencephalograms, which measure electrical activity in the brain] can be used,” she says. “The patients can be asked questions and given two things to think about for answers: playing tennis for yes, walking around in their house for no. And different parts of their brain will light up. People can be conscious while appearing outwardly unconscious.”
The end-result could mean reassessing the quality of life, Johnson says. Some patients can be asked—the so-called “covertly aware” patients who are conscious but can communicate only with technological assistance.
“Just as importantly, we might be able to use technology to objectively measure aspects of quality of life even in patients who cannot communicate at all,” Johnson says.
The ethical issues loom.
“A person’s quality of life is inherently subjective, and the aim of quality of life assessment has always been to find ways to objectively measure that subjective state of being,” she says. “New technologies like fMRI might be able to provide a different kind of objective assessment of subjective wellbeing—by looking at brain activity—in those individuals who are unable to tell us how they’re doing.”
Psychologists report new insights on human brain, consciousness
UCLA psychologists have used brain-imaging techniques to study what happens to the human brain when it slips into unconsciousness. Their research, published Oct. 17 in the online journal PLOS Computational Biology, is an initial step toward developing a scientific definition of consciousness.
"In terms of brain function, the difference between being conscious and unconscious is a bit like the difference between driving from Los Angeles to New York in a straight line versus having to cover the same route hopping on and off several buses that force you to take a ‘zig-zag’ route and stop in several places," said lead study author Martin Monti, an assistant professor of psychology and neurosurgery at UCLA.
Monti and his colleagues used functional magnetic resonance imaging (fMRI) to study how the flow of information in the brains of 12 healthy volunteers changed as they lost consciousness under anesthesia with propofol. The participants ranged in age from 18 to 31 and were evenly divided between men and women.
The psychologists analyzed the “network properties” of the subjects’ brains using a branch of mathematics known as graph theory, which is often used to study air-traffic patterns, information on the Internet and social groups, among other topics.
"It turns out that when we lose consciousness, the communication among areas of the brain becomes extremely inefficient, as if suddenly each area of the brain became very distant from every other, making it difficult for information to travel from one place to another," Monti said.
The finding shows that consciousness does not “live” in a particular place in our brain but rather “arises from the mode in which billions of neurons communicate with one another,” he said.
When patients suffer severe brain damage and enter a coma or a vegetative state, Monti said, it is very possible that the sustained damage impairs their normal brain function and the emergence of consciousness in the same manner as was seen by the life scientists in the healthy volunteers under anesthesia.
"If this were indeed the case, we could imagine in the future using our technique to monitor whether interventions are helping patients recover consciousness," he said.
"It could, however, also be the case that losing consciousness because of brain injury affects brain function through different mechanisms," said Monti, whose research team is currently addressing this question in another study.
"As profoundly defining of our mind as consciousness is, without having a scientific definition of this phenomenon, it is extremely difficult to study," Monti noted. This study, he said, marks an initial step toward conducting neuroscience research on consciousness.
The research was conducted at Belgium’s University Hospital of Liege.
Monti’s expertise includes cognitive neuroscience, the relationship between language and thought, and how consciousness is lost and recovered after severe brain injury. He was part of a team of American and Israeli brain scientists who used fMRI on former Israeli Prime Minister Ariel Sharon in January 2013 to assess his brain responses.
Surprisingly, Sharon, who was presumed to be in a vegetative state since suffering a brain hemorrhage in 2006, showed significant brain activity, Monti and his colleagues reported.
The former prime minister was scanned to assess the extent and quality of his brain processing, using methods recently developed by Monti and his colleagues. The scientists found subtle but encouraging signs of consciousness.
Suited for treatment of brain damage
For those with brain damage or neurological disorders, treatment could be as close as the wardrobe.
An alternative to painful treatments and surgery for brain damage may now be available with a specially-designed elastic body suit fitted with electrodes, which was designed at KTH Royal Institute of Technology in collaboration with health care and business partners.
The Mollii garment could improve range of motion and reduce pain for people with brain injuries and neurological disorders such as MS and cerebral palsy.
The garment provides the body with electrical stimulation to ease tension and spasms. The result is reduced pain perception and increased mobility.
The idea originated with a Swedish chiropractor, Fredrik Lundqvist, who worked with rehabilitation of brain-damaged patients. Lundqvist struck upon the idea of sewing electrical stimuli – similar to TENS (transcutaneous electrical nerve stimulation) electrodes – into garments that the patient can wear.
He turned to KTH researchers Johan Gawell and Jonas Wistrand at the Department of Machine Design. “They produced a prototype of the product, and today they are working full time on the development of Mollii,” Lundqvist says.
“We need more engineers in care,” Lundqvist says. “I believe that dedicated, young people who are passionate about the future should be given a free hand to develop innovations.”
Designed with ordinary swimsuit material, the body suit has conductive elastic sewn into it, with electrodes located at the major muscles.
Battery-powered light current is conducted via silver wires to 58 electrodes attached to the inside of the garment, which in turn stimulate as many as distinct 42 muscles, according to the patient’s needs.
Batteries are placed in a small control box fitted at the waistband.
“The idea is that the clothes should be used for a few hours, three times a week, and the effect is expected to last for up to two days,” Lundqvist says.
Users are advised engage in movement through training and stretching during the treatment.
“To enhance the quality of life the patient may choose to use Mollii before it’s time to go to work, school or to a social event. That enables the body to function as well as possible when it is really needed,” he says.
The garment has been shown to be highly effective in patient examinations performed in collaboration with a PhD student Stockholm’s Karolinska Institute, Lundvist says. “One-hundred percent of the participants in the survey say they have experienced improvements in existing function or quality of life,” he says.
Stroke patients with paralysis on one side have been found to gain increased mobility in spastic limbs, in that they had improved gait and their arms and hands worked better after treatment.
“As a bonus, the patients often sleep better, and their pharyngeal motor skills and speech improved after using Mollii,” Lundqvist says.
The treatment of patients with movement difficulties and pain due to neurological damage can often require surgery, injections of botolinumtoxin (neurotoxin) or strong medications.
“These treatments mean high costs and side effects, while our clothes are simple and safe to use,” Lundqvist says. “You can reduce the number of hospital visits because the therapy can be performed at home. And when the mobility increases, there is less need for walkers or wheelchairs.”
Mollii is an approved CE marked medical device, but independent clinical tests have yet been performed. But the company behind the treatment, Inerventions, has launched a scientific study of the clinical effectiveness of the garment, in partnership with Rehab Medical clinics in Linköping and Borås. Lundqvist says the results should come next year.
Today, Mollii is available through the Swedish health care system as a personal tool prescribed by physical or occupational therapists. And the garment can also be purchased directly from Inerventions.
The price is about EUR 5,600 for two years guaranteed spasticity treatment. If the suit during that time becomes too small, the patient can switch to a new, tested garment at no additional cost.
In Denmark, the garment is already subsidized with municipal funds for treatment of nerve damage, based on recommendations from a physiotherapist.
Inerventions’ goal is to establish Mollii in Europe, the U.S. and Japan. The garment can in the future be used to help patients with chronic pain and people with Restless Legs Syndrome (RLS).
“It can also help children with physical disabilities or motor difficulties in the feet, such as constantly walking on toes or with their feet at inward angles,” Lundqvist says.
Recombinant Human Prion Protein Inhibits Prion Propagation
Case Western Reserve University researchers today published findings that point to a promising discovery for the treatment and prevention of prion diseases, rare neurodegenerative disorders that are always fatal. The researchers discovered that recombinant human prion protein stops the propagation of prions, the infectious pathogens that cause the diseases.
“This is the very first time recombinant protein has been shown to inhibit diseased human prions,” said Wen-Quan Zou, MD, PhD, senior author of the study and associate professor of pathology and neurology at Case Western Reserve School of Medicine.
Recombinant human prion protein is generated in E. coli bacteria and it has the same protein sequence as normal human brain protein. But different in that, the recombinant protein lacks attached sugars and lipids. In the study, published online in Scientific Reports, researchers used a method called protein misfolding cyclic amplification which, in a test-tube, mimics the prions’ replication within the human brain. The propagation of human prions was completely inhibited when the recombinant protein was added into the test-tube. The researchers found that the inhibition is dose-dependent and highly specific in responding to the human-form of the recombinant protein, as compared to recombinant mouse and bovine prion proteins. They demonstrated that the recombinant protein works not only in the cell-free model but also in cultured cells, which are the first steps of translational research. Further, since the recombinant protein has an identical sequence to the brain protein, the application of the recombinant protein is less likely to cause side effects.
Prion diseases are a group of fatal transmissible brain diseases affecting both humans and animals. Prions are formed through a structural change of a normal prion protein that resides in all humans. Once formed, they continue to recruit other normal prion protein and finally cause spongiform-like damage in the brain. Currently, the diseases have no cure.
Previous outbreaks of mad cow disease and subsequent occurrences of the human form, variant Creutzfeldt–Jakob disease, have garnered a great deal of public attention. The fear of future outbreaks makes the search for successful interventions all the more urgent.
(Source: casemed.case.edu)
Stem cells help repair traumatic brain injury by building a “biobridge”
University of South Florida researchers have suggested a new view of how stem cells may help repair the brain following trauma. In a series of preclinical experiments, they report that transplanted cells appear to build a “biobridge” that links an uninjured brain site where new neural stem cells are born with the damaged region of the brain.
Their findings were recently reported online in the peer-reviewed journal PLOS ONE.
“The transplanted stem cells serve as migratory cues for the brain’s own neurogenic cells, guiding the exodus of these newly formed host cells from their neurogenic niche towards the injured brain tissue,” said principal investigator Cesar Borlongan, PhD, professor and director of the USF Center for Aging and Brain Repair.
Based in part on the data reported by the USF researchers in this preclinical study, the U.S. Food and Drug Administration recently approved a limited clinical trial to transplant SanBio Inc’s SB632 cells (an adult stem cell therapy) in patients with traumatic brain injury.
Stem cells are undifferentiated, or blank, cells with the potential to give rise to many different cell types that carry out different functions. While the stem cells in adult bone marrow or umbilical cord blood tend to develop into the cells that make up the organ system from which they originated, these multipotent stem cells can be manipulated to take on the characteristics of neural cells.
To date, there have been two widely-held views on how stem cells may work to provide potential treatments for brain damage caused by injury or neurodegenerative disorders. One school of thought is that stem cells implanted into the brain directly replace dead or dying cells. The other, more recent view is that transplanted stem cells secrete growth factors that indirectly rescue the injured tissue.
The USF study presents evidence for a third concept of stem-cell mediated brain repair.
The researchers randomly assigned rats with traumatic brain injury and confirmed neurological impairment to one of two groups. One group received transplants of bone marrow-derived stem cells (SB632 cells) into the region of the brain affected by traumatic injury. The other (control group) received a sham procedure in which solution alone was infused into the brain with no implantation of stem cells.
At one and three months post-TBI, the rats receiving stem cell transplants showed significantly better motor and neurological function and reduced brain tissue damage compared to rats receiving no stem cells. These robust improvements were observed even though survival of the transplanted cells was modest and diminished over time.
The researchers then conducted a series of experiments to examine the host brain tissue.
At three months post-traumatic brain injury, the brains of transplanted rats showed massive cell proliferation and differentiation of stem cells into neuron-like cells in the area of injury, the researchers found. This was accompanied by a solid stream of stem cells migrating from the brain’s uninjured subventricular zone — a region where many new stem cells are formed – to the brain’s site of injury.
In contrast, the rats receiving solution alone showed limited proliferation and neural-commitment of stem cells, with only scattered migration to the site of brain injury and virtually no expression of newly formed cells in the subventricular zone. Without the addition of transplanted stem cells, the brain’s self-repair process appeared insufficient to mount a defense against the cascade of traumatic brain injury-induced cell death.
The researchers conclude that the transplanted stem cells create a neurovascular matrix that bridges the long-distance gap between the region in the brain where host neural stem cells arise and the site of injury. This pathway, or “biobridge,” ferries the newly emerging host cells to the specific place in the brain in need of repair, helping promote functional recovery from traumatic brain injury.
New Study Shows How ICU Ventilation May Trigger Mental Decline
Researchers from Penn Medicine and University of Oviedo Identify Molecular Pathway Linking ICU Ventilation to Brain Damage
At least 30 percent of patients in intensive care units (ICUs) suffer some form of mental dysfunction as reflected in anxiety, depression, and especially delirium. In mechanically-ventilated ICU patients, the incidence of delirium is particularly high, about 80 percent, and may be due in part to damage in the hippocampus, though how ventilation is increasing the risk of damage and mental impairment has remained elusive.
Now, a new study published in the American Journal of Respiratory and Critical Care Medicine fromresearchers at the University of Oviedo in Spain, St. Michael’s Hospital in Toronto, Canada, and the Perelman School of Medicine at the University Pennsylvaniafound a molecular mechanism that may explain the connection between mechanical ventilation and hippocampal damage in ICU patients.
The investigators, including Adrian González-López, PhD, in the laboratory of Guillermo M. Albaiceta, MD, PhD at the University of Oviedo , and co-authored by Konrad Talbot, PhD, an assistant research professor in Neurobiology in the Department of Psychiatry at Penn Medicine, began by studying the hippocampus in control mice and in mice on low or high-pressure mechanical ventilation for 90 minutes. Compared to the controls, those on either low- or high-pressure ventilation showed evidence of neuronal cell death in the hippocampus, as a result of a cell suicide program called apoptosis.
Searching for the molecular cause of the ventilation-induced apoptosis, the team discovered that a well-known apoptosis trigger had been set off in the hippocampus of the ventilated animals. That trigger is dopamine-induced suppression of a molecule known as Akt, which normally acts to prevent neuronal apoptosis. Akt suppression was clearly evident in the hippocampus of the ventilated mice and was associated with a hyperdopaminergic state (increased levels of dopamine) in that brain area. The ventilated mice had elevated gene expression of the enzyme tyrosine hydroxylase, which is critical in synthesizing dopamine. The resulting rise in dopamine increases the strength of dopamine receptor activation in the hippocampus.
The investigators hypothesized that ventilation-induced apoptosis in the hippocampus was at least partly mediated by elevated activation of dopamine receptors in that brain area. This was confirmed by showing that pretreatment of mice with type 2 (D2) dopamine receptor blockers injected into the ventricles of the brain significantly reduced ventilation-induced apoptosis in the hippocampus.
How mechanical ventilation manages to affect the hippocampus was answered by experiments on mice in which the vagus cranial nerve connecting the lungs with the brain was severed. In these mice, mechanical ventilation had virtually no effect on levels of the dopamine-synthesizing enzyme or on apoptosis in the hippocampus.
The investigators then studied the consequences of ventilation and elevated hippocampal dopamine on dysbindin-1, a protein known to affect levels of cell surface D2 dopamine receptors, cognition, and possibly the risk of psychosis. High-pressure ventilation in mice caused an increase in gene expression of dysbindin-1C, and later, in protein levels of dysbindin-1C. Dopamine alone had similar effects on dysbindin-1C in hippocampal slice preparations, effects that were inhibited by D2 receptor blockers.
Since dysbindin-1 can lower cell-surface D2 receptors and protect against apoptosis, the authors speculate that increased dysbindin-1C expression in the ventilated mice may reflect compensatory responses to ventilation-induced hippocampal apoptosis. That possibility applies to ICU cases given the additional finding by the authors that total dysbindin-1 was increased in hippocampal neurons of ventilated compared to non-ventilated humans who died in the ICU.
The findings could lead to new therapeutic uses of established drugs and targets for new drugs that activate a molecular pathway mediating adverse effects of ICU ventilation on brain function.
“The results prove the existence of a pathogenic mechanism of lung stretch-induced hippocampal apoptosis that could explain the development of neurobehavioral disorders in patients exposed to mechanical ventilation,” the authors write. One of the coauthors, Dr. Talbot, adds: “The study indicates the need to reevaluate use of D2 receptor antagonists in minimizing the negative cognitive effects of mechanical ventilation in ICU patients and to evaluate the novel possibility that elevation in dysbindin-1C expression can also reduce those effects.”
The corresponding author, Dr. Albaiceta, offered a look at future research on this topic: “Now that we have established the mouse model, we are mainly looking for therapeutic approaches aimed at avoiding the vagal activation caused by mechanical ventilation and therefore prevent the deleterious effects observed in the hippocampus,” he said. “We are also interested in studying the relationship between the different described gene polymorphisms of dysbindin, Akt, and type 2 dopamine receptor versus the incidence of neurological disorders in patients on ventilation in ICUs. This could help us to identify susceptible individuals to in which a preventive treatment could be effective.”
(Source: uphs.upenn.edu)