Better Stroke Care, Everywhere: Study Boosts Local Hospitals' Clotbuster Use

Dec. 20, 2012 — From the moment a stroke occurs, patients must race against the clock to get treatment that can prevent lasting damage. Now, a new study shows the promise -- and the challenges -- of getting them state-of-the-art treatment safely at their local hospital, saving precious minutes.

The results come from an effort that tested methods to improve delivery of a time-sensitive, clot-busting drug in stroke patients at 24 community hospitals across Michigan. To date, clot-busting treatment has been mostly used at larger hospitals.

The research effort was coordinated by members of the University of Michigan Health System's Department of Emergency Medicine, Department of Neurology and Stroke Program, which offered half the hospitals education and round-the-clock treatment assistance by phone. The study was funded by the National Institute of Neurological Disorders and Stroke at the National Institutes of Health.

By the end of the study, the community hospitals across Michigan that had the U-M experts as the "sixth man" on their teams did better at delivering the drug called tPA to eligible patients than those that didn't.

The findings of the randomized controlled trial are published in Lancet-Neurology. They show that community hospitals can indeed improve patients' chances of getting tPA in the first few hours of a stroke, without increased risk of dangerous bleeding.

Data from 22 of the hospitals show that tPA use more than doubled in the 11 hospitals that were randomly chosen to get the extra help, versus a smaller increase in the 11 that didn't. Some hospitals even surpassed national targets for tPA use that large stroke centers don't always reach -- a true game-changing performance.

Across the U.S., less than 2 percent of stroke patients receive tPA -- when more than 11 percent could -- largely because of the time limits on its use and delays in getting patients to a hospital. That's why it's important for community hospitals to offer it.

The investigation, called INSTINCT for INcreasing Stroke Treatment through INterventional Change Tactics, demonstrates that tPA can be used safely and appropriately in the community hospital setting -- and that more work needs to be done to expand public access to the only treatment approved by the U.S. Food and Drug Administration to reverse the effects of stroke. While improvement at the target community hospitals that got the education was statistically significant, it was not as large as hoped for. But the findings suggest that relatively low-cost and low-tech interventions can improve local stroke care.

Lead author Phillip Scott, M.D., a U-M emergency physician and principal investigator of the trial, likens the results to the performance of teams from smaller athletic conferences that beat larger, more celebrated teams, to reach the final stages of the annual NCAA college basketball tournament.

"This study suggests that community hospitals can evaluate and treat enough emergency stroke patients to keep their teams' treatment skills sharp, but are of a size that creates rapid lines of communication and stable physican and nurse teams. This may facilitate rapid, safe stroke diagnosis and care," says Scott, an associate professor of emergency medicine at the U-M Medical School. "Four of the hospitals that received the educational intervention achieved tPA use rates of 5 to 8 percent of all stroke patients, compared to only one of the control hospitals. That's a rate many large medical centers strive to reach."

"This study, while finding only modest improvements, provides encouraging evidence that intensive professional education at community hospitals has the potential to improve the use of tPA in acute stroke care," said Scott Janis, Ph.D., program director at the NINDS. "Importantly, it also lays the groundwork for future strategies that should be explored to develop evidence-based interventions that would improve patient access to this proven therapy following stroke."

How it was done, and more about the results:

The study started by collecting baseline data on stroke treatment from 2005 and 2006 at all the hospitals. After the sites were randomized, the U-M team offered continuing medical education classes at the hospitals, workshops at U-M, and other support, including 24-hour phone consultation availability, to the hospitals chosen to receive the intervention.

All the hospitals were in the lower peninsula of Michigan, and were chosen at random from among hospitals with at least 100 stroke discharges per year. All hospitals that participated stayed in the trial until data collection ended in 2010. Hospitals could hold primary stroke center designation, as granted by the Joint Commission, but could not be tertiary academic comprehensive stroke centers.

In all, 188 tPA treatments occurred among 15,065 stroke patients during the baseline period, and 557 treatments occurred among 25,758 stroke patients from 2007 to 2010. The authors note that tPA use at hospitals nationwide rose somewhat during the study period, due to factors such as insurance reimbursement and new data on tPA's effectiveness at preventing disability.

The INSTINCT study findings were complicated by the fact that one of the hospitals enrolled in the trial became an academic stroke center after starting the study. When it and its matched hospital are excluded from the analysis, the remaining hospitals showed enough of an impact from the educational effort to be statistically significant -- a 105 percent increased use of tPA over baseline.

"We essentially saw a doubling of tPA usage, using standard technologies for education and support. Importantly, the increase was achieved safely," Scott says. "This shows we can translate the knowledge of effective stroke treatment into a community setting." The size of the study, with 557 stroke patients treated after intervention began, makes it one of the largest tPA studies in the world.

More about stroke treatment:

The use of tPA in ischemic stroke has grown around the world in the last decade, but many patients who could get the drug still do not. The "treatment window" for tPA has been seen as three hours from the onset of stroke symptoms, though recent studies suggest patients can see benefit even four and a half hours out. The importance of early treatment, however, cannot be overstated, as patients treated earlier have greater benefits and the drug is not currently FDA-approved for use beyond three hours.

Considering that most stroke sufferers wait more than an hour after symptoms start before they seek help, and that travel time to a tPA-providing hospital is around 30 minutes, that leaves hospitals about an hour to do medical imaging, make a firm diagnosis and initiate tPA treatment.

Patients must then be monitored to check for brain bleeding, and to assess the impact of their stroke. To reliably accomplish this, a system for the care of acute stroke patients must already be in place when a patient arrives at the emergency department.

Patients who don't reach a location where they can received standard tPA treatment in time can still potentially be treated with advanced catheter-based clot removal treatment at a major referral hospital such as U-M. These advanced therapies have a longer time window for treatment, but have not been proven more effective than early standard treatment. The Stroke Program at U-M is participating in multiple trials to improve advanced stroke treatment.

Additional authors: William Meurer, M.D., Shirley Frederiksen, M.S., and Robert Silbergleit, M.D. of U-M Emergency Medicine; John Kalbfleisch, Ph.D., Zhenzhen Xu, Ph.D. and Mary Haan, DrPH of the U-M School of Public Health; and Lewis B Morgenstern, M.D., of U-M Neurology. Morgenstern directs, and Scott, Meurer, Frederiksen and Silbergleit are members of, the U-M Stroke Program.

Funding source: NINDS R01-NS-050372

Alzheimer's Plaques in PET Brain Scans Identify Future Cognitive Decline

Among patients with mild or no cognitive impairment, brain scans using a new radioactive dye can detect early evidence of Alzheimer's disease that may predict future decline, according to a multi-center study led by researchers at Duke University Medical Center.


The finding is published online July 11, 2012, in the journal Neurology, the medical journal of the American Academy of Neurology. It expands on smaller studies demonstrating that early detection of tell-tale plaques could be a predictive tool to help guide care and treatment decisions for patients with Alzheimer's disease.

"Even at a short follow-up of 18 months we can see how the presence of amyloid plaques affects cognitive function," said P. Murali Doraiswamy, M.D., professor of psychiatry at Duke who co-led the study with R. Edward Coleman, M.D., professor of radiology at Duke . "Most people who come to the doctor with mild impairment really want to know the short-term prognosis and potential long-term effect."

Doraiswamy said such knowledge also has some pitfalls. There is no cure for Alzheimer's disease, which afflicts 5.4 million people in the United States and is the sixth-leading cause of death among U.S. adults. But he said numerous drugs are being investigated, and identifying earlier disease would improve research into their potential benefits and speed new discoveries, while also enhancing care and treatment of current patients.

In the Neurology study, 151 people who had enrolled in a multi-center test of a new radioactive dye called florbetapir (Amyvid) were recruited to participate in a 36-month analysis. Of those participants, 69 had normal cognitive function at the start of the study, 51 had been diagnosed with mild impairment, and 31 had Alzheimer's dementia.

All completed cognitive tests and underwent a brain scan using Positron Emission Tomography, or PET imaging. The technology uses radioactive tracers designed to highlight specific tissue to create a three-dimensional picture of an organ or a biological function.

The dye used in the study, florbetapir, was recently approved by the U.S. Food and Drug Administration for PET imaging of the brain to estimate beta-amyloid plaque density in patients who are being evaluated for cognitive impairment. It binds to the amyloid plaques that characterize Alzheimer's disease, providing a window into the brain to see if the plaques have formed, and how extensively.

Patients in the study were reassessed with additional cognitive exams at 18 months and 36 months. At the 18-month point, patients with mild cognitive impairment who had PET evidence of plaque at the trial's start worsened to a great degree on cognitive tests than patients who had no evidence of plaque at the trial's start. Twenty-nine percent of the plaque-positive patients in this group developed Alzheimer's dementia, compared to 10 percent who started with no plaque.

Cognitively normal patients with a plaque-positive PET scan at the start of the study also showed more mental decline at 18 months compared to those who were negative for plaque.

The study additionally found that people with negative scans reversed from minimally impaired to normal more often than people with positive PET scan, suggesting test anxiety or concentration problems could have affected their initial performance.

"For the most part we have been blind about who would progress and who wouldn't, so this approach is a step toward having a biomarker that predicts risk of decline in people who are experiencing cognitive impairment," Doraiswamy said.

He said the study's results provide initial data that needs to be verified by additional research. Final, 36-month data from the study has been completed and will be presented at the Alzheimer's Association International Conference this week in Vancouver, Canada. Doraiswamy also cautioned that florbetapir is currently not approved to predict the development of dementia or other neurologic conditions and stressed that it should not be used as a screening tool in otherwise normal or minimally impaired people. Likewise, a positive scan is not necessarily diagnostic for Alzheimer's by itself.

In addition to Doraiswamy and Coleman (who died in June), study authors included; Reisa A. Sperling and Keith A. Johnson of Massachusetts General Hospital, Boston Medical School; Eric M. Reiman of Banner Alzheimer's Institute; Mat D. Davis of the University of Pennsylvania; Michael Grundman of Global R&D Partners and the University of California, San Diego; Marwan N. Sabbagh of Banner-Sun Health Research Institute; Carl H. Sadowsky of Nova SE University; Adam S. Fleisher of Banner Alzheimer's Institute and UCSD; and Alan Carpenter, Christopher M. Clark (deceased), Abhinay D. Joshi, Mark A. Mintun, Daniel M. Skovronsky, and Michael J. Pontecorvo of Avid Radiopharmaceuticals.

The study was funded by Eli Lilly/Avid Radiopharmaceuticals, which markets florbetapir and conducted by Avid and the AV45-A11 study group, a consortium of Alzheimer's clinical research centers. Doraiswamy receives advisory and speaker fees from Lilly/Avid, as well as other companies, and owns shares in Sonexa and Clarimedix.

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A. Why is memory screening so important?



Ø As the body ages, so does the brain, especially the ability to remember declines. There are many reasons that cause memory loss; stress, depression, vitamin deficiency, thyroid problems, medical illnesses, Alzheimer’s disease, or just normal aging memory decline.



Ø Memory screenings are the first step toward finding out if the person has early stages of Alzheimer’s dementia vs another condition vs normal aging memory decline.



Ø It is very important to identify the disease or problem that is causing memory loss. Early detection leads to early treatment, which in turn, leads to improved quality of life



Ø Memory screenings can also let the person know that everything is ok. The screenings could turn out normal and put the mind at ease.



Ø Normal scores on a memory screenings provides a valuable opportunity to establish a baseline score for future comparison



Ø A memory screening is not used to diagnose any particular illness & does not replace consultation with a qualified physician or health care provider



B. What is the process of memory screenings?



Ø A screening consists of a series of questions and tasks that are designed to test memory and thinking ability. These tools are non-invasive, safe, and reliable instruments that are sensitive to even mild brain dysfunction

Ø Feedback will be provided immediately following screenings.

Ø While health plans do not typically cover screenings, if additional testing is recommended, most health plans will cover the cost based on individual medical benefits. If necessary, referrals will be provided to seek further examination.



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New Biomarker In The Blood May Help Predict Alzheimer's Disease

ScienceDaily (July 18, 2012) — Higher levels of a certain fat in the blood called ceramides may increase a person's risk of developing Alzheimer's disease, according to a study published in the July 18, 2012, online issue of Neurology®, the medical journal of the American Academy of Neurology.

"Our study identifies this biomarker as a potential new target for treating or preventing Alzheimer's disease," said study author Michelle M. Mielke, PhD, an epidemiologist with the Mayo Clinic in Rochester, Minn. Mielke was with Johns Hopkins University at the time of the research.


For the study, 99 women between the ages of 70 and 79 and free of dementia in the Women's Health and Aging Study II had their blood tested for levels of serum ceramides, a fatty compound found throughout the body that is associated with inflammation and cell death. The participants were placed into three groups: high, middle and low levels of ceramides. They were then followed for up to nine years. Of the 99 participants, 27 developed dementia and 18 of those were diagnosed with probable Alzheimer's disease.


The study found that women who had the highest levels of the biomarker were 10 times more likely to develop Alzheimer's disease than women with the lowest levels. Those with middle levels of the biomarker were nearly eight times more likely to develop the disease than those with the lowest levels.
"These findings are important because identifying an accurate biomarker for early Alzheimer's that requires little cost and inconvenience to a patient could help change our focus from treating the disease to preventing or delaying it," said Valory Pavlik, PhD, with the Alzheimer's Disease and Memory Disorders Center of Baylor College of Medicine in Houston and a member of the American Academy of Neurology, in an accompanying editorial.


According to Pavlik, "While a larger, more diverse study is needed to confirm these findings, projections that the global prevalence of Alzheimer's disease will double every 20 years for the foreseeable future have certainly increased the sense of urgency among researchers and health care agencies to identify more effective screening, prevention and treatment strategies."
The study was supported by the National Institute on Aging, the National Institute of Neurological Disorders and Stroke and the Johns Hopkins Older Americans Independence Center.

Adaptable Decision Making In The Brain 

ScienceDaily (June 19, 2012) — Researchers at the University of Iowa, together with colleagues from the California Institute of Technology and New York University, have discovered how a part of the brain helps predict future events from past experiences. The work sheds light on the function of the front-most part of the frontal lobe, known as the frontopolar cortex, an area of the cortex uniquely well developed in humans in comparison with apes and other primates.

Making the best possible decisions in a changing and unpredictable environment is an enormous challenge. Not only does it require learning from past experience, but it also demands anticipating what might happen under previously unencountered circumstances. Past research from the UI Department of Neurology was among the first to show that damage to certain parts of the frontal lobe can cause severe deficits in decision making in rapidly changing environments. The new study from the same department on a rare group of patients with damage to the very frontal part of their brains reveals a critical aspect of how this area contributes to decision making. The findings were published June 19 in the Journal of Neuroscience.

"We gave the patients four slot machines from which to pick in order to win money. Unbeknownst to the patients, the probability of getting money from a particular slot machine gradually and unpredictably changed during the experiment. Finding the strategy that pays the most in the long run is a surprisingly difficult problem to solve, and one we hypothesized would require the frontopolar cortex," explains Christopher Kovach, Ph.D., a UI post-doctoral fellow in neurosurgery and first author of the study.

Contrary to the authors' initial expectation, the patients actually did quite well on the task, winning as much money, on average, as healthy control participants.

"But when we compared their behavior to that of subjects with intact frontal lobe, we found they used a different set of assumptions about how the payoffs changed over time," Kovach says. "Both groups based their decisions on how much they had recently won from each slot machine, but healthy comparison subjects pursued a more elaborate strategy, which involved predicting the direction that payoffs were moving based on recent trends. This points towards a specific role for the frontopolar cortex in extrapolating recent trends."



Kovach's colleague and study author Ralph Adolphs, Ph.D., professor of neuroscience and psychology at the California Institute of Technology, adds that the study results "argue that the frontopolar cortex helps us to make short-term predictions about what will happen next, a strategy particularly useful in environments that change rapidly -- such as the stock market or most social settings."



Adolphs also hold an adjunct appointment in the UI Department of Neurology.



The study's innovative approach to understanding the function of this part of the brain uses model-based analyses of behavior of patients with specific and precisely characterized areas of brain damage. These patients are members of the UI's world-renowned Iowa Neurological Patient Registry, which was established in 1982 and has more than 500 active members with selective forms of damage, or lesions, to one or two defined regions in the brain.



"The University of Iowa is one of the few places in the world where you could carry out this kind of study, since it requires carefully assessed patients with damage to specific parts of their brain," says study author Daniel Tranel, Ph.D., UI professor of neurology and psychology and director of the UI Division of Behavioral Neurology and Cognitive Neuroscience.



In a final twist to the finding, the strategy taken by lesion patients was actually slightly better than the one used by comparison subjects. It happened that the task was designed so that the trends in the payoffs were, in fact, random and uninformative.


"The healthy comparison subjects seemed to perceive trends in what was just random noise," Kovach says.



This implies that the functions of the frontopolar cortex, which support more complex and detailed models of the environment, at times come with a downside: setting up mistaken assumptions.



"To the best of my knowledge this is the first study which links a normal tendency to see a nonexistent pattern in random noise, a type of cognitive bias, to a particular brain region," Kovach notes.



The researchers next want to investigate other parts of the frontal cortex in the brain, and have also begun to record activity directly from the brains of neurosurgical patients to see how single cells respond while making decisions. The work is also important to understand difficulties in decision making seen in disorders such as addiction.



The study, "Anterior prefrontal cortex contributes to action selection through tracking of recent reward trends," also included authors David Rudrauf from the University of Iowa, John O'Doherty from the California Institute of Technology, and Nathaniel Daw from New York University.

Breaking Point: When Does Head Trauma in Sports Lead to Memory Loss?

ScienceDaily (Apr. 18, 2012) — A new study suggests there may be a starting point at which blows to the head or other head trauma suffered in combat sports start to affect memory and thinking abilities and can lead to chronic traumatic encephalopathy, or CTE, in the brain.



The research was released April 18 and will be presented as part of the Emerging Science program at the American Academy of Neurology's 64th Annual Meeting in New Orleans April 21 to April 28, 2012.

"While we already know that boxing and other combat sports are linked to brain damage, little is known about how this process develops and who may be on the path to developing CTE, which is a degenerative brain disease found in athletes and others with a history of multiple concussions and brain damage," said study author Charles Bernick, MD, of the Cleveland Clinic in Cleveland and a member of the American Academy of Neurology. CTE is only diagnosed through autopsy after death, but symptoms include memory loss, aggression and difficulty thinking.

The study involved 35 boxers and 43 mixed martial arts athletes with an average age of 29 who were part of the ongoing Professional Fighters Brain Health Study. The fighters were given computer tests that measured memory and thinking skills and underwent MRI brain scans. Years of fighting and number of fights were recorded based on self-reporting and published records. The fighters were then split into two groups: those who fought for nine or fewer years and those with more than nine years of fighting history.

In both groups, those with more years of fighting and more fights per year were more likely to have lower brain volumes in three areas of the brain. In those with fewer than nine years of fighting, there was no relationship between the years of fighting or the number of fights per year and the results on memory and thinking tests. But for those who had fought for nine or more years, those with more fights per year performed worse on the thinking and memory tests than those with fewer fights per year.

"Our study shows there appears to be a threshold at which continued repetitive blows to the brain begin to cause measurable changes in memory and thinking, despite brain volume changes that can be found earlier," said Bernick.

The study was supported by the Lincy Foundation.

Physical Activity May Reduce Alzheimer’s Disease Risk at Any Age

ScienceDaily (Apr. 18, 2012) — Daily physical activity may reduce the risk of Alzheimer's disease and cognitive decline, even in people over the age of 80, according to a new study by neurological researchers from Rush University Medical Center that will be published in the online issue of Neurology, the medical journal of the American Academy of Neurology on April 18.


"The results of our study indicate that all physical activities including exercise as well as other activities such as cooking, washing the dishes, and cleaning are associated with a reduced risk of Alzheimer's disease," said Dr. Aron S. Buchman, lead author of the study and associate professor of neurological sciences at Rush. "These results provide support for efforts to encourage all types of physical activity even in very old adults who might not be able to participate in formal exercise, but can still benefit from a more active lifestyle."

"This is the first study to use an objective measurement of physical activity in addition to self-reporting," said Dr. Aron S. Buchman, lead author of the study and associate professor of neurological sciences at Rush. "This is important because people may not be able to remember the details correctly."

To measure total daily exercise and non-exercise physical activity, researchers from Rush asked 716 older individuals without dementia with an average age of 82 to wear a device called an actigraph, which monitors activity, on their non-dominant wrist continuously for 10 days.

All exercise and non-exercise physical activity was recorded. Study participants also were given annual cognitive tests during this ongoing study to measure memory and thinking abilities. Participants also self-reported their physical and social activities. Study participants were individuals from the Rush Memory and Aging Project, an ongoing, longitudinal community study of common chronic conditions of old age.

Over a mean of 3.5 years of follow-up, 71 participants developed Alzheimer's disease The research found that people in the bottom 10 percent of daily physical activity were more than twice as likely (2.3 times) to develop Alzheimer's disease as people in the top 10 percent of daily activity.

The study also showed that those individuals in the bottom 10 percent of intensity of physical activity were almost three times (2.8 times) as likely to develop Alzheimer's disease as people in the top percent of the intensity of physical activity.

"Since the actigraph was attached to the wrist, activities like cooking, washing the dishes, playing cards and even moving a wheelchair with a person's arms were beneficial," said Buchman. "These are low-cost, easily accessible and side-effect free activities people can do at any age, including very old age, to possibly prevent Alzheimer's."

The number of Americans older than 65 years of age will double to 80 million by 2030. "Our study shows that physical activity, which is an easily modifiable risk factor, is associated with cognitive decline and Alzheimer's disease. This has important public health consequences," said Buchman.

Co-authors of the study from Rush are Patricia Boyle, PhD; Li Yu, PhD; Dr. Raj C. Shah; Robert S. Wilson, PhD; and Dr. David A. Bennett.

The National Institutes of Health, National Institute on Aging, the Illinois Department of Public Health and the Robert C. Borwell Endowment Fund helped fund the study.

New Medication Offers Hope to Patients With Frequent, Uncontrollable Seizures

ScienceDaily (Apr. 18, 2012) — A new type of anti-epilepsy medication that selectively targets proteins in the brain that control excitability may significantly reduce seizure frequency in people whose recurrent seizures have been resistant to even the latest medications, new Johns Hopkins-led research suggests. "Many other drugs to treat frequent seizures have been released in the last 10 years and for many people, they just don't work," says study leader Gregory L. Krauss, M.D., a professor of neurology at the Johns Hopkins University School of Medicine. "For a drug-resistant population that has run out of options, this study is good news. These are patients who are tough to treat and are fairly desperate."


Perampanel is the first in a new class of drugs that appears to blunt an excitatory response in the brain by inhibiting a specific form of glutamate receptor called an AMPA receptor and therefore reducing seizures without causing major side effects. Other drugs targeting all three forms of glutamate receptors in the brain have tended to make patients too sleepy to function, even putting them in comas, Krauss says. But this new medication, he says, may potentially offer relief not only to people with epilepsy, but to those struggling with drug addiction problems or the neurodegenerative disorder ALS.

"For years, people have been trying to modify glutamate receptors to cure disease," he says. "It's been a very difficult area to develop new drugs in."

In a multinational, blinded, placebo-controlled trial of more than 700 people with uncontrolled partial-onset seizures, roughly one-third of participants saw the frequency of their seizures fall by more than 50 percent when they were given 8 milligrams a day of perampanel. Partial-onset seizures -- the most common form in epilepsy -- begin in one part of the brain, occurring when there is an injury or abnormality in one of the brain's electrical networks. They can involve anything from the twitching of a limb to confusion to convulsions. Those in this trial typically had roughly 10 seizures a day at baseline.

One in 200 Americans have epilepsy and more than half have partial-onset seizures.

The participants in the study, being reported this week in the journal Neurology, were all taking one to three anti-epileptic drugs before adding perampanel (or a placebo) to their regimen. Krauss and his colleagues assigned each to receive a placebo, two milligrams, four milligrams or eight milligrams per day of the drug. The lowest effective dose was four milligrams per day and the higher the dose, they found, the better the results. Another trial is currently looking at a 12 milligram per day dose. The most common side effect was dizziness, Krauss says.

The study was paid for by Eisai Inc., a New Jersey-based pharmaceutical firm. Krauss says he believes the U.S. Food and Drug Administration will review perampanel in the next year.

Training Can Improve Memory and Increase Brain Activity in Mild Cognitive Impairment

Science Daily (Mar. 1, 2012) — If someone has trouble remembering where the car keys or the cheese grater are, new research shows that a memory training strategy can help. Memory training can even re-engage the hippocampus, part of the brain critical for memory formation, the results suggest.



Researchers at Emory University School of Medicine and Atlanta Veterans Affairs Medical Center have been investigating memory-building strategies for people with MCI (mild cognitive impairment). The techniques used in the study were known to be effective for healthy people, but it has been uncertain how they could affect brain function in people with MCI.

The results are published online in the journal Hippocampus.


"Our results suggest that these strategies can help patients remember specific information, such as the locations of objects, " says lead author Benjamin Hampstead, PhD, assistant professor of rehabilitation medicine at Emory University School of Medicine. "This is the first randomized controlled trial to show that these techniques are not only effective in MCI patients, but that they can also re-engage the hippocampus, which is a brain region that is critical for forming new memories."

Hampstead is a clinical neuropsychologist at the Atlanta VA Rehabilitation, Research and Development Center of Excellence. Study co-authors included Krish Sathian, MD, PhD, professor of neurology, rehabilitation medicine, and psychology, and director of the Rehabilitation R&D Center of Excellence at the Atlanta VAMC; and Anthony Stringer, PhD, professor of rehabilitation medicine and psychology.

MCI is a diagnosis meant to identify those at increased risk of eventually converting to Alzheimer's disease. People with MCI have difficulty forming new memories but are still able to handle tasks of daily living. The difficulty learning and remembering new information is because of impaired function in parts of the brain including the hippocampus.

The study focused on how well participants could remember the locations of common household objects. The memory-building strategy involves three steps. First, participants focused on a feature of the room that stood out and was close to the object, then they learned a short explanation for why the object was in that location. Finally, they created a mental picture to tie the information together.

In several sessions, study participants were shown household objects one at a time, each object followed by its location in a computer-simulated room. An hour later, they were asked to identify the location of each object from among three choices.

After the first visit, participants returned to the laboratory for three training sessions. On a fifth visit two weeks later, they were evaluated on how well they could remember the objects' locations. A control group received the same amount of exposure to the objects and their locations, but was not given explicit training.

As expected, at the start of the study MCI patients had more difficulty remembering where objects were and showed less brain activity in the hippocampus (measured through functional magnetic resonance imaging) when compared with healthy people.

Both people with MCI and healthy controls benefited significantly more from using memory strategies than from mere exposure. In addition, MCI patients in the memory strategy-training group showed increased activity in the hippocampus as they learned and remembered the location of the objects. Participants in the training group showed increases in hippocampal activity, even when trying to remember the locations of new objects.

"This is an initial, albeit encouraging, step in determining methods that can help these patients function better in their everyday lives," says Stringer, who originally developed the strategies on which training in this study was based.

"These techniques may hold particular promise given that they appear to promote neuroplastic changes in key brain regions," Sathian says.

The Emory/VA team has also tested the effectiveness of the memory-building techniques for associating faces and names, in another set of studies. They are continuing the study of the memory-building techniques, with the aim of determining how long the benefits of training last, and whether participants can use the strategies independently outside the laboratory.

The research was supported by the Department of Veterans Affairs and the National Institute on Aging, part of the National Institutes of Health.

New High Definition Fiber Tracking Reveals Damage Caused by Traumatic Brain Injury

Science Daily (Mar. 2, 2012) — A powerful new imaging technique called High Definition Fiber Tracking (HDFT) will allow doctors to clearly see for the first time neural connections broken by traumatic brain injury (TBI) and other neurological disorders, much like X-rays show a fractured bone, according to researchers from the University of Pittsburgh in a report published online in the Journal of Neurosurgery.



In the report, the researchers describe the case of a 32-year-old man who wasn't wearing a helmet when his all-terrain vehicle crashed. Initially, his CT scans showed bleeding and swelling on the right side of the brain, which controls left-sided body movement. A week later, while the man was still in a coma, a conventional MRI scan showed brain bruising and swelling in the same area. When he awoke three weeks later, the man couldn't move his left leg, arm and hand.

"There are about 1.7 million cases of TBI in the country each year, and all too often conventional scans show no injury or show improvement over time even though the patient continues to struggle," said co-senior author and UPMC neurosurgeon David O. Okonkwo, M.D., Ph.D., associate professor, Department of Neurological Surgery, Pitt School of Medicine. "Until now, we have had no objective way of identifying how the injury damaged the patient's brain tissue, predicting how the patient would fare, or planning rehabilitation to maximize the recovery."


HDFT might be able to provide those answers, said co-senior author Walter Schneider, Ph.D., professor of psychology at Pitt's Learning Research and Development Center (LRDC), who led the team that developed the technology. Data from sophisticated MRI scanners is processed through computer algorithms to reveal the wiring of the brain in vivid detail and to pinpoint breaks in the cables, called fiber tracts. Each tract contains millions of neuronal connections.

"In our experiments, HDFT has been able to identify disruptions in neural pathways with a clarity that no other method can see," Dr. Schneider said. "With it, we can virtually dissect 40 major fiber tracts in the brain to find damaged areas and quantify the proportion of fibers lost relative to the uninjured side of the brain or to the brains of healthy individuals. Now, we can clearly see breaks and identify which parts of the brain have lost connections."


HDFT scans of the study patient's brain were performed four and 10 months after he was injured; he also had another scan performed with current state-of the-art diffusion tensor imaging (DTI), an imaging modality that collects data points from 51 directions, while HDFT is based on data from 257 directions. For the latter, the injury site was compared to the healthy side of his brain, as well as to HDFT brain scans from six healthy individuals.

Only the HDFT scan identified a lesion in a motor fiber pathway of the brain that correlated with the patient's symptoms of left-sided weakness, including mostly intact fibers in the region controlling his left leg and extensive breaks in the region controlling his left hand. The patient eventually recovered movement in his left leg and arm by six months after the accident, but still could not use his wrist and fingers effectively 10 months later.

Memory loss, language problems, personality changes and other brain changes occur with TBI, which the researchers are exploring with HDFT in other research protocols.

UPMC neurosurgeons also have used the technology to supplement conventional imaging, noted Robert Friedlander, M.D., professor and chair, Department of Neurological Surgery, Pitt School of Medicine, and UPMC Endowed Professor of Neurosurgery and Neurobiology. He is not a member of this research study.

"I have used HDFT scans to map my approach to removing certain tumors and vascular abnormalities that lie in areas of the brain that cannot be reached without going through normal tissue," he said. "It shows me where significant functional pathways are relative to the lesion, so that I can make better decisions about which fiber tracts must be avoided and what might be an acceptable sacrifice to maintain the patient's best quality of life after surgery."


Dr. Okonkwo noted that the patient and his family were relieved to learn that there was evidence of brain damage to explain his ongoing difficulties. The team continues to evaluate and validate HDFT's utility as a brain imaging tool, so it is not yet routinely available.

"We have been wowed by the detailed, meaningful images we can get with this technology," Dr. Okonkwo said. "HDFT has the potential to be a game-changer in the way we handle TBI and other brain disorders."

Co-authors include lead author Samuel L. Shin, Ph.D., Allison J. Hricik, M.S., Megan Maserati, and Ava M. Puccio, Ph.D., all of the Department of Neurological Surgery; Timothy Verstynen, Ph.D., Sudhir Pathak, M.S., and Kevin Jarbo, all of LRDC; and Sue R. Beers, of the Department of Psychiatry, all of the University of Pittsburgh.

The study was funded by the Defense Advanced Research Projects Agency

When One Side Does Not Know About the Other One: Specialization and Cooperation of the Brain Hemispheres

Science Daily (Mar. 2, 2012) — Whenever we are doing something, one of our brain hemispheres is more active than the other one. However, some tasks are only solvable with both sides working together. PD Dr. Martina Manns and Juliane Römling of the Ruhr-Universität Bochum are investigating, how such specializations and co-operations arise. Based on a pigeon-model, they are demonstrating for the first time in an experimental way, that the ability to combine complex impressions from both hemispheres, depends on environmental factors in the embryonic stage.


Within the egg bird embryos always turn their head in such a way that one eye is turned close to the eggshell, and the other one is covered by the body. This causes an asymmetrical light stimulation, which influences developmental processes in both brain halves. PD Dr. Manns uses this mechanism for her experiment. One group of embryos hatch in a lighted incubator, another one in complete darkness. Afterwards the scientists analyze the degree of interhemispheric communication in both groups. The results show that information exchange is impaired without light-stimulation. This research sheds light on the origin of communication processes in the brain. Developmental disorders like ADHD or autism are characterized by a deviating pattern between the two brain halves. Therefore, there is a possibility that the results may help to understand those disorders and give hints for new therapeutic approaches.


Classification of colour-pairs

To determine how efficient the animals are able to handle incoming information, Manns and Römling confront the animals with a task that can only be solved with both brain hemispheres working together. For that purpose, the two psychologists use colour-pairs of a transitive line(A>B>C>D>E) at which one of the elements is rewarded with food. First the pigeons have to learn to discriminate the combinations A/B and B/C with one eye, and C/D and D/E with the other one. Afterwards, they can use both eyes to decide between, for example, the colours B/D. However, only birds with embryonic light experience are able to solve this problem.

Eating Berries Benefits the Brain

Science Daily (Mar. 7, 2012) — Strong scientific evidence exists that eating blueberries, blackberries, strawberries and other berry fruits has beneficial effects on the brain and may help prevent age-related memory loss and other changes, scientists report. Their new article on the value of eating berry fruits appears in ACS' Journal of Agricultural and Food Chemistry.


Barbara Shukitt-Hale, Ph.D., and Marshall G. Miller point out that longer lifespans are raising concerns about the human toll and health care costs of treating Alzheimer's disease and other forms of mental decline. They explain that recent research increasingly shows that eating berry fruits can benefit the aging brain. To analyze the strength of the evidence about berry fruits, they extensively reviewed cellular, animal and human studies on the topic.


Their review concluded that berry fruits help the brain stay healthy in several ways. Berry fruits contain high levels of antioxidants, compounds that protect cells from damage by harmful free radicals. The two also report that berry fruits change the way neurons in the brain communicate. These changes in signaling can prevent inflammation in the brain that contribute to neuronal damage and improve both motor control and cognition. They suggest that further research will show whether these benefits are a result of individual compounds shared between berry fruits or whether the unique combinations of chemicals in each berry fruit simply have similar effects.

Overeating May Double Risk of Memory Loss

ScienceDaily (Feb. 13, 2012) — New research suggests that consuming between 2,100 and 6,000 calories per day may double the risk of memory loss, or mild cognitive impairment (MCI), among people age 70 and older.


The study was just released and will be presented at the American Academy of Neurology's 64th Annual Meeting in New Orleans April 21 to April 28, 2012. MCI is the stage between normal memory loss that comes with aging and early Alzheimer's disease.

"We observed a dose-response pattern which simply means; the higher the amount of calories consumed each day, the higher the risk of MCI," said study author Yonas E. Geda, MD, MSc, with the Mayo Clinic in Scottsdale, Arizona and a member of the American Academy of Neurology.


The study involved 1,233 people between the ages of 70 and 89 and free of dementia residing in Olmsted County, Minn. Of those, 163 had MCI. Participants reported the amount of calories they ate or drank in a food questionnaire and were divided into three equal groups based on their daily caloric consumption. One-third of the participants consumed between 600 and 1,526 calories per day, one-third between 1,526 and 2,143 and one-third consumed between 2,143 and 6,000 calories per day.

The odds of having MCI more than doubled for those in the highest calorie-consuming group compared to those in the lowest calorie-consuming group. The results were the same after adjusting for history of stroke, diabetes, amount of education, and other factors that can affect risk of memory loss. There was no significant difference in risk for the middle group.

"Cutting calories and eating foods that make up a healthy diet may be a simpler way to prevent memory loss as we age," said Geda.


The co-authors of the study include Ronald C. Petersen, MD, Fellow of the American Academy of Neurology, and other investigators of the Mayo Clinic Study of Aging in Rochester, Minn.

The study was supported by the National Institutes of Health, the Robert Wood Johnson Foundation and the Robert H. and Clarice Smith and Abigail van Buren Alzheimer's Disease Research Program.

Good Aerobic Capacity Promotes Learning

Aerobic fitness has a favorable effect on cognitive functions. For example, physically active elderly people are less prone to aging-related cognitive decline than those who lead a sedentary lifestyle. An increase in physical activity raises both aerobic capacity and learning ability in both humans and animals. However, it is not known whether it is the aerobic capacity or the pleasure and enrichment of physical activity that promotes cognitive functions.



A study conducted by research groups at the University of Jyväskylä shows that aerobic fitness -- not physical activity as such -- promotes cognitive abilities.

- In this study, we used rat strains raised at the University of Michigan. They had been selectively bred over 23 generations for their endurance running capacity. Due to this breeding, there were natural-born long-distance runners and very poor runners. Results from a test that is a counterpart to the human maximal endurance test indicate that the difference between these strains was 500%, says Heikki Kainulainen, Professor of Exercise Physiology.

- Rats were trained in a discrimination learning test that measures flexible cognition. They were first taught to fetch a food reward in the presence of one tone and to ignore the other one. After learning this rule, the stimulus assignment was reversed and they were required to abandon the old rule and learn a new one, describes Dr. Jan Wikgren, Senior Researcher at the Department of Psychology.


It was found that rats with intrinsically high aerobic capacity clearly outperformed those with intrinsically low aerobic capacity. It must be emphasized that the animals were not given any physical exercise before the learning test. Thus, the results suggest that it is the aerobic capacity and not physical activity alone that is related to flexible cognition.

The results gave rise to many questions. Probably the most crucial seeks to determine the neurobiological mechanisms that mediate the effect of aerobic capacity on brain function.


- In future experiments we aim at studying the possible differences between these strains from the molecular to neurophysiological levels of analysis. Ultimately, we hope to investigate plausible exercise interventions that protect the brain from the detrimental effects of aging, Wikgren and Kainulainen explain. At least it is safe to say that physical activity is good for your brain at any age.

Novel Brain Tumor Vaccine Acts Like Bloodhound to Locate Cancer Cells

ScienceDaily (Jan. 5, 2012) — A national clinical trial testing the efficacy of a novel brain tumor vaccine has begun at Wake Forest Baptist Medical Center, the only facility in the Southeast to participate. The vaccine will be tested in patients with newly diagnosed glioblastoma multiforme (GBM), the most aggressive and highest grade malignant glioma. Wake Forest Baptist will treat a minimum of 25 patients in this randomized, placebo-controlled phase II clinical trial of ICT-107. A total of 20 sites across the country are participating in the trial to test the safety and efficacy of this novel cancer vaccine.


All patients enrolled in the study will receive the current standard treatment for GBM, which includes surgery followed by radiation and chemotherapy. Two thirds of the participants will then also get the experimental vaccine treatment, which will be administered in the post radiation phase of treatment, while the others will get a "dummy," or placebo vaccine in addition to standard therapy.

"This vaccine is for newly-diagnosed patients," said Glenn Lesser, M.D., a professor of internal medicine, hematology-oncology, at Wake Forest Baptist and principal investigator for the study. "Scientifically, it's a very well designed study and we are excited to participate in this clinical trial. We've been asked to participate based on our reputation as an outstanding brain tumor center and the expertise our center has with bringing novel therapies and novel therapeutics to patients."


The approach with this particular vaccine is unique, Lesser added, because it is targeting the antigens or proteins that are present on glioma stem cells, whereas other treatment approaches mostly target differentiated tumor cells.

"The antigens used in this vaccine target the tumor stem cells -- the handful of cells that keep the tumor alive and dividing. Most of the cells we kill with standard treatment are likely not the ones driving the tumor growth. If the stem cells aren't targeted, they keep generating more tumors."


According to the biotechnology company that is conducting the trial, the Phase I clinical study of ICT-107 in GBM involved 16 newly-diagnosed patients who received the vaccine in addition to standard therapy -- surgery, radiation and chemotherapy. Those patients demonstrated a one-year overall survival of 100 percent and a two-year survival of 80 percent. Although only a small number of patients were treated, these results compare favorably with historical 61percent one-year and 26 percent two-year survival with standard care alone.

Vaccines for brain tumors are new and experimental, said Lesser, but are gaining more attention in the glioma world. "Vaccines are a way to harness the body's own defenses -- which are usually used to ward off or control infections like the flu -- to fight cancer cells instead," Lesser explained. "It is a way of presenting antigens or proteins normally found on the surface of the cancer cells to the immune system so that immune cells can seek out and kill those cancer cells anywhere in the body. This is not unlike giving a piece of clothing to a bloodhound and then letting it loose to find a missing person."


Wake Forest Baptist is also involved in another brain tumor vaccine trial for patients with low-grade or slower growing gliomas. Among the targets of both of these vaccines is a new protein found on the surface of glioma cells discovered by Waldemar Debinski, M.D., Ph.D, director of the Wake Forest Baptist Brain Tumor Center of Excellence.

"Early studies of vaccines for patients with brain tumors are showing promising results," Lesser said. "We want to help definitively determine how good these novel therapies really are for patients."

What Determines the Capacity of Short-Term Memory?

ScienceDaily (Dec. 15, 2011) — Short-term memory plays a crucial role in how our consciousness operates. Several years ago a hypothesis has been formulated, according to which capacity of short-term memory depends in a special way on two cycles of brain electric activity. Scientists from the Nencki Institute of Experimental Biology of the Polish Academy of Sciences in Warsaw have now demonstrated this experimentally for the first time.


A human being can consciously process from five to nine pieces of information simultaneously. During processing these pieces of information remain in the short-term memory. In 1995 researchers from Brandeis University in Waltham suggested that the capacity of short-term memory could depend on two bands of brain's electric activity: theta and gamma waves. However, only now, through carefully designed experiments conducted at the Nencki Experimental Biology Institute of the Polish Academy of Sciences (Nencki Institute) in Warsaw, it was possible to unambiguously prove that such a relationship really exists.


For an electroencephalography exam (EEG) several electrodes are placed on patient's head. The recorded brain electric signals contain waves of different frequencies, among other theta waves with the frequency of 4-7 Hz and gamma waves with the frequency of 25-50 Hz. It has been known for some time that these waves are used for retaining information in the brain. It was observed for example that the amplitudes of theta and gamma waves increased when people were forced to store more information in short-term memory.

"The hypothesis formulated by Lisman and Idiart in 1995 assumes that we are able to memorise as many 'bites' of information, as there are gamma cycles for one theta cycle. Research to date provided only indirect support for this hypothesis," say psychologist Jan Kamiński, PhD student from the Nencki Institute and main author of experiments conducted by the team of Prof. Andrzej Wróbel in cooperation with Dr. Aneta Brzezicka from the Warsaw School of Social Sciences and Humanities.


A 'bite' of information refers to its portion in memory. A 'bite' may be a number, letter, idea, situation, picture or smell. "Designing experiments on the capacity of memory one needs to be very careful not to make it too easy for the subject to group many 'bites' into one," stresses Kamiński and as an example gives the following sequence of letters: 2, 0, 1, 1. "Such four 'bites' of information are easy to group into the number corresponding to current year. Instead of four bites of information we are left with just one."

Interpreting the length of theta and gamma waves from EEG recording is not easy either. These waves are not directly visible in the EEG signal. Kamiński proposed a new method of determining them. Researchers recorded brain's electric activity in seventeen volunteers resting with closed eyes for five minutes. Next they filtered the signals and analysed not the cycles themselves but their correlations. Only based on discovered correlations the ratio of the length of theta wave to gamma wave was determined and the likely capacity of verbal short-term memory was determined.


Following the EEG recording, the volunteers, were subjected to classic short-term memory capacity test. It consisted of repeated display of longer and longer sequences of numbers. Each number was presented for one second. Then volunteers had to reconstruct the sequence from memory. At first the sequence consisted of three numbers but at the end of the exam of as many as nine. "We have observed that the longer the theta cycles, the more information 'bites' the subject was able to remember; the longer the gamma cycle, the less the subject remembered. Next we determined the correlation between the results of the tests and estimates from the EEG measurements. Just as expected the correlation turned out to be very high and it confirmed the hypothesis of Lisman and Idiart," says Kamiński.


Capacity of short-term memory impacts the effects of reasoning -- the greater the capacity, the better the effects. Currently researchers conduct studies on developing the most effective ways of training short-term memory.