Scientists develop world's most advanced drug to protect the brain after a stroke

Scientists at the Toronto Western Research Institute (TWRI), Krembil Neuroscience Center, have developed a drug that protects the brain against the damaging effects of a stroke in a lab setting. This drug has been in development for a few years. At this point, it has reached the most advanced stage of development among drugs created to reduce the brain's vulnerability to stroke damage (termed a "neuroprotectant"). Over 1000 attempts to develop such drugs by scientists worldwide have failed to be translated to a stage where they can be used in humans, leaving a major unmet need for stroke treatment. The drug developed by the TWRI team is the first to achieve a neuroprotective effect in the complex brain of primates, in settings that simulate those of human strokes. ischemic stroke.
The study, "Treatment of Stroke with a PSD95 inhibitor in the Gyrencephalic Primate Brain", published online today in Nature, shows how the drug, called a "PSD95 inhibitor" prevents brain cell death and preserves brain function when administered after a stroke has occurred.
"We are closer to having a treatment for stroke than we have ever been before," said Dr. Michael Tymianski, TWRI Senior Scientist and the study's lead author. "Stroke is the leading cause of death and disability worldwide and we believe that we now have a way to dramatically reduce its damaging effects."
During a stroke, regions of the brain are deprived of blood and oxygen. This causes a complex sequence of chemical reactions in the brain, which can result in neurological impairment or death. The PSD95 inhibitor published by the Toronto team acts to protect the brain by preventing the occurrence of these neurotoxic reactions.
The study used cynomolgus macaques, which bear genetic, anatomic and behaviour similarities to humans, as an ideal model to determine if this therapy would be beneficial in patients.
Animals that were treated with the PSD95 inhibitor after a stroke had greatly reduced brain damage and this translated to a preservation of neurological function. These improvements were observed in several scenarios that simulated human strokes. Specifically, when the treatment was given either early, or even at 3 hours, after the stroke onset, the animals exhibited remarkable recoveries. Benefits were also observed when the drug therapy was combined with conventional therapies (aimed at re-opening blocked arteries to the brain). Beneficial effects were observed even in a time window when conventional therapies on their own no longer have an effect.
"There is hope that this new drug could be used in conjunction with other treatments, such as thrombolytic agents or other means to restore blood flow to the brain, in order to further reduce the impact of stroke on patients," said Dr. Tymianski. "These findings are extremely exciting and our next step is to confirm these results in a clinical trial."
More information: DOI: 10.1038/nature10841
Provided by University Health Network

"Scientists develop world's most advanced drug to protect the brain after a stroke." February 29th, 2012. http://medicalxpress.com/news/2012-02-scientists-world-advanced-drug-brain.html

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Robert Karl Stonjek

Study finds new genes that cause Baraitser-Winter syndrome, a brain malformation

Scientists from Seattle Children's Research Institute and the University of Washington, in collaboration with the Genomic Disorders Group Nijmegen in the Netherlands, have identified two new genes that cause Baraitser-Winter syndrome, a rare brain malformation that is characterized by droopy eyelids and intellectual disabilities.
"This new discovery brings the total number of genes identified with this type of brain defect to eight," said William Dobyns, MD, a geneticist at Seattle Children's Research Institute. Identification of the additional genes associated with the syndrome make it possible for researchers to learn more about brain development. The study, "De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome," was published online February 26 in Nature Genetics.
The brain defect found in Baraitser-Winter syndrome is a smooth brain malformation or "lissencephaly," as whole or parts of the surface of the brain appear smooth in scans of patients with the disorder. Previous studies by Dr. Dobyns and other scientists identified six genes that cause the smooth brain malformation, accounting for approximately 80% of affected children. Physicians and researchers worldwide have identified to date approximately 20 individuals with Baraitser-Winter syndrome.
While the condition is rare, Dr. Dobyns said the team's findings have broad scientific implications. "Actins, or the proteins encoded by the ACTB and ACTG1 genes, are among the most important proteins in the function of individual cells," he said. "Actins are critical for cell division, cell movement, internal movement of cellular components, cell-to-cell contact, signaling and cell shape," said Dr. Dobyns, who is also a University of Washington professor of pediatrics. "The defects we found occur in the only two actin genes that are expressed in most cells," he said. Gene expression is akin to a "menu" for conditions like embryo development or healing from an injury. The correct combination of genes must be expressed at the right time to allow proper development. Abnormal expression of genes can lead to a defect or malformation.
"Birth defects associated with these two genes also seem to be quite severe," said Dr. Dobyns. "Children and people with these genes have short stature, an atypical facial appearance, birth defects of the eye, and the smooth brain malformation along with moderate mental retardation and epilepsy. Hearing loss occurs and can be progressive," he said.
Dr. Dobyns is a renowned researcher whose life-long work has been to try to identify the causes of children's developmental brain disorders such as Baraitser-Winter syndrome. He discovered the first known chromosome abnormality associated with lissencephaly (Miller-Dieker syndrome) while still in training in child neurology at Texas Children's Hospital in 1983. That research led, 10 years later, to the discovery by Dobyns and others of the first lissencephaly gene known as LIS1.
More information:
"De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome": http://www.nature. … ng.1091.html
"Baraitser-Winter syndrome" study slideshow: http://www.flickr. … 29446519959/
"Baraitser-Winter syndrome" studies: "Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats" http://www.ncbi.nl … med/8355785; "doublecortin, a Brain-Specific Gene Mutated in Human X-Linked Lissencephaly and Double Cortex Syndrome, Encodes a Putative Signaling Protein" http://www.ncbi.nlm.nih.gov/pubmed/9489700
Provided by Seattle Children's

"Study finds new genes that cause Baraitser-Winter syndrome, a brain malformation." February 29th, 2012. http://medicalxpress.com/news/2012-02-genes-baraitser-winter-syndrome-brain-malformation.html

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Robert Karl Stonjek

Effects of a concussion may last longer than symptoms, study shows

Director of the UK Concussion Assessment Research Lab Scott Livingston (bottom left) shows the results of MEP testing to UK men's soccer player Marco Bordon. Credit: University of Kentucky Public Relations

A study recently published by the University of Kentucky's Scott Livingston shows that physiological problems stemming from a concussion may continue to present in the patient even after standard symptoms subside.
Currently, concussions are diagnosed and monitored through a patient's self-reported symptoms (including headache, confusion or disorientation, poor concentration, and memory loss) and through computerized neuropsychological testing programs, which measure cognitive abilities including attention and concentration, cognitive processing, learning and memory, and verbal fluency. Post-concussion abnormalities in either of these markers typically return to a normal level within five to 10 days following the injury.
Conducted while he was a graduate student at the University of Virginia, Livingston's study was just published in the February 2012 issue of the Journal of Clinical Neurophysiology. The study used motor-evoked potentials (MEPs) — an electrophysiological measurement that can provide hard evidence for changes in brain function — to determine if any physiological abnormalities followed a similar recovery pattern to self-reported symptoms and neuropsychological testing.
During an MEP test, subjects have electrodes placed on a limb – such as the hand or foot. A magnetic stimulating device is placed over the head, and they receive a brief pulse of magnetic stimulation to the brain. The "reaction time" — the amount of time it takes for the subject's limb to receive the response from the brain after the stimulation — is recorded.
Livingston's study enrolled 18 collegiate athletes — nine who had been concussed within the previous 24 hours, and nine who had not experienced a concussion. Each concussed subject was matched with a non-concussed subject using age, gender, sport, position played, prior concussion history, and history of learning disability or attention deficit-hyperactivity disorder as inclusion criteria.
Subjects were evaluated for evidence of concussion based on self-reported symptoms, computerized neurocognitive test performance, and MEPs for a period of 10 days. Post-concussion symptoms were more frequent and greater in severity in the immediate timeframe after the injury (24-72 hours) and decreased in the following days. Some subjects reported no symptoms by day 10, though others did not have complete symptoms resolution by that time. Neurocognitive deficits followed a similar pattern, proving greater just after the injury and returning to normal (or closer to normal) by day 10.
MEPs, however, showed delays in response time and smaller MEP size which continued up to day 10, with these physiological changes actually increasing as the concussed athletes' symptoms decreased and cognitive functioning improved.

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The University of Kentucky's Scott Livingston discusses preseason baseline testing for concussions in athletes. A recently published study performed by Livingston while he was at the University of Virginia used motor-evoked potential testing to show evidence that the physiological effects of a concussion may last longer than its symptoms. Livingston's research lab at UK recently began a new program to study motor-evoked potentials in athletes pre- and post-concussion. At UK, all athletes who participate in a contact sport — including football, soccer, volleyball, diving, gymnastics, and basketball — are assessed preseason using MEP and neurocognitive testing to estbalish a baseline measure for each athlete. If an athlete receives a concussion, he or she will come back to the lab as soon as possible after the injury for follow-up testing. This approach allows researchers to get a clearer idea of the extent of an athlete's injury. Credit: University of Kentucky Public Relations

Livingston, director of the UK Concussion Assessment Research Lab and assistant professor in the Department of Rehabilitation Sciences, says these findings are significant for both athletes and sports medicine clinicians.
"Further investigation of MEPs in concussed athletes is needed, especially to assess how long the disturbances in physiological functioning continue after those initial ten days post-injury," Livingston said. "But in the meantime, sports medicine personnel caring for concussed athletes should be cautious about relying solely on self-reported symptoms and neurocognitive test performances when making return-to-play decisions."
Livingston's research lab recently began a new program to further study MEPs in athletes pre- and post-concussion. At UK, all athletes who participate in a contact sport — including football, soccer, volleyball, diving, gymnastics, and basketball — are assessed preseason using MEP and neurocognitive testing to establish a baseline measure for each athlete.
If an athlete receives a concussion, he or she will come back to the lab as soon as possible after the injury for follow-up testing. This approach allows researchers to get a clearer idea of the extent of an athlete's injury, Livingston says.
Neurocognitive tests, such as the Immediate Post-Concussion Assessment and Testing (ImPACT)™, are a valuable component of concussion management. While major professional sports organizations like the NFL and NHL, as well as hundreds of colleges, universities, and high schools across the United States follow this standard, UK Athletics did not have a formal, standardized neurocognitive testing protocol in place until last year. The addition of the MEP assessment in the preseason testing and post-concussion management are unique — UK is the first and only collegiate athletics program to implement a baseline physiologic measure of brain function.
"No other college of university in the country is currently assessing physiologic brain responses and using this information to determine the extent of the functional brain injury," Livingston said. "This type of information enables us to closely track recovery, which may not correspond to the decrease in concussion symptoms or recovery of memory and other cognitive functions."
Provided by University of Kentucky

"Effects of a concussion may last longer than symptoms, study shows." February 29th, 2012. http://medicalxpress.com/news/2012-02-effects-concussion-longer-symptoms.html

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Robert Karl Stonjek