New vaccine shown promise in preventing secondary strokes after an ischemic stroke

New research published in journal Hypertension shows that vaccine called S100A9 may be able to replace oral blood thinners to reduce the risk of secondary strokes in patients with recent ischemic stroke.

Japanese researchers successfully tested an experimental vaccine in mice and found that it provided protection against blood clots for more than two months without increasing the risk of bleeding or causing an autoimmune response.

The vaccine, S100A9, inhibits blood clot formation and, during the study, protected the arteries of treated mice from forming new clots for more than two months, and additionally, worked as well as the oral blood thinner clopidogrel in a major artery, according to Hironori Nakagami, M.D., Ph.D., study co-author and professor at Osaka University, in Japan.

“Many stroke patients don’t take their blood thinning drugs as prescribed, which makes it more likely they will have another stroke. This vaccine might one day help solve this issue since it would only need to be injected periodically,” Nakagami said.

Citation: Tomohiro Kawano, M.D.; Munehisa Shimamura, M.D., Ph.D.; Tatsuya Iso, M.D., Ph.D.; Hiroshi Koriyama, M.D., Ph.D.; Shuko Takeda; Tsutomu Sasaki, M.D., Ph.D.; Manabu Sakaguchi, M.D., Ph.D.; Ryuichi Morishita, M.D., Ph.D.; and Hideki Mochizuki, M.D., Ph.D.
https://doi.org/10.1161/STROKEAHA.118.022837

Understanding molecular mechanisms behind germinal matrix hemorrhage

Researchers have utilized a mouse model to determine the molecular mechanisms underlying germinal matrix hemorrhage. Nearly 12,000 premature infants born annually in the US are affected by neonatal brain hemorrhage which results in mortality and long-term morbidity. Unfortunately, no treatment exists for this condition, and the only preventive measure is steroids before birth, which has deleterious effects on brain development. The hemorrhage originates from the rupture of small brain vessels in a highly fragile region known as the germinal matrix.

However, the cellular and molecular mechanisms of this disorder remain poorly understood. In a recent study led by Drs. Jui Dave and Daniel Greif at Yale University found that mutant embryonic mice lacking the gene, Alk5 in pericytes (cells that support small brain vessels) develop germinal matrix hemorrhage. The condition arises due to enhanced proliferation of endothelial cells and upregulated protease activity which result in vessel rupture and hemorrhage. Furthermore, the study reveals that treating mutant mice with a recombinant protein, TIMP3 effectively attenuates the hemorrhage and reduces bleeding. The study is published in the journal Developmental Cell.

The findings from this study provide novel insights into the pathogenesis of germinal matrix hemorrhage and are likely to shed light on other brain disorders such as stroke and aneurysms as well. Although further research is needed to fully understand the beneficial effects of TIMP3, this study promises to broaden the scope of therapeutic intervention for this devastating disorder.

Citation: Dave, Jui M., Teodelinda Mirabella, Scott D. Weatherbee, and Daniel M. Greif. “Pericyte ALK5/TIMP3 Axis Contributes to Endothelial Morphogenesis in the Developing Brain.” Developmental Cell, 2018. doi:10.1016/j.devcel.2018.01.018.

Researchers propose video game therapy to improve mobility in stroke patients

Researchers at the Basque Center on Cognition, Brain and Language (BCBL) in San Sebastian and the London Imperial College have analyzed the architecture of brain injuries in stroke patients. Based on the findings researchers propose new therapy using video games for mobility problems. The study is published in the PNAS journal.

According to the BCBL expert David Soto, “patients with brain injuries in attention control areas also suffer motility control problems, even when the movement required by the task is very simple”.

The scientists focused on exploring the extent and location of brain injuries in 167 stroke patients for more than three years. Through a ‘mapping’ performed with magnetic resonance, they identified the affected part and the type and size of the lesion, and analyzed the connectivity between the different areas of the brain. Next, they subjected the patients to various motor tasks, some very simple, such as grabbing an object with force. After the tests, the researchers found that these tasks were “impaired” in those patients who had injuries in the area of the brain “involved” in attention.

The experts emphasize the importance of the brain areas related with attention control in the control of movements, which “may also suggest some therapeutic routes”, such as complementing “mobility therapies based on physiotherapy with another type of cognitive training that increases the attention of patients”. One example would be the work with video games.

David Soto explains that before this study it was thought that the control of movement and the attention control aspect were “different systems” with little relation to each other, and that the treatments enabled for the patients with cognitive injuries could not serve for those who had mobility problems. However, the conclusions of this research have shown otherwise.

“We have to know first how our brain controls and moves to design effective therapeutic tools for stroke patients and specific therapies for each individual depending on where the injury has occurred,” concludes Soto.

To confirm these results, the next step will be to establish a clinical trial with patients suffering motor skills disorders due to a stroke and divide them into two groups: one of them undergoing physiotherapy treatment and the other with complementary cognitive training.

Citation: Rinne, Paul, Mursyida Hassan, Cristina Fernandes, Erika Han, Emma Hennessy, Adam Waldman, Pankaj Sharma, David Soto, Robert Leech, Paresh A. Malhotra, and Paul Bentley. “Motor dexterity and strength depend upon integrity of the attention-control system.” Proceedings of the National Academy of Sciences 115, no. 3 (2017). doi:10.1073/pnas.1715617115.

Adapted from press release by FECYT – Spanish Foundation For Science and Technology.

Increased risk of cardiovascular events in HIV patients

Current methods to predict the risk of heart attack and stroke vastly underestimate the risk in individuals with HIV, which is nearly double that of the general population, reports a new Northwestern Medicine study. “The actual risk of heart attack for people with HIV was roughly 50 percent higher than predicted by the risk calculator many physicians use for the general population,” said first author Dr. Matthew Feinstein, a cardiovascular disease fellow at Northwestern University Feinberg School of Medicine. The study was published in JAMA Cardiology.

The higher risk for heart attack about 1.5 to two times greater exists even in people whose virus is undetectable in their blood because of antiretroviral drugs. Accurately predicting an individual’s risk helps determine whether he or she should take medications such as statins to reduce the risk of heart attack or stroke.

The study was conducted using a large, multi-center clinical cohort of HIV-infected individuals receiving care at one of five participating sites around the country. Researchers analyzed data from approximately 20,000 HIV-infected individuals. They compared predicted rates of heart attacks based on data from the general population to the actual rates of heart attacks observed in this cohort.

Scientists believe that primary driver of the higher risk is the HIV-related chronic inflammation. Plaque buildup occurs 10 to 15 years earlier in HIV patients than in the uninfected population. In addition to inflammation and other effects from the virus as factors in higher heart attack and stroke rates, senior study author Dr. Heidi Crane also pointed to higher rates of traditional risk factors like smoking.

“Despite these differences, we found that risk scores developed in the general population — while not as accurate as we would like are still useful in assessing risk in HIV populations,” said Crane, associate professor of medicine at the University of Washington. “More research is needed to develop better ways to assess risk in HIV. “

Feinstein and colleagues hope to collaborate with a large multi-center HIV cohort to develop a new algorithm. They attempted to do it with this study, but 20,000 patients weren’t enough for an accurate predictor. The current tool for predicting heart attack risk for the general population is based on more than 200,000 patients.

“Regardless of age, sex or race, the risks are higher in people with HIV,” Feinstein said. Of HIV-infected groups, the study found the current predictor tool was least accurate in African American men and women and most effective for Caucasian men.

A clinical trial is underway at Northwestern Medicine to evaluate how well common medications for heart disease prevention and treatment, such as statin medications, work to prevent heart disease in the HIV-infected population.

Citation: Feinstein, Matthew J., Robin M. Nance, Daniel R. Drozd, Hongyan Ning, Joseph A. Delaney, Susan R. Heckbert, Matthew J. Budoff, William C. Mathews, Mari M. Kitahata, Michael S. Saag, Joseph J. Eron, Richard D. Moore, Chad J. Achenbach, Donald M. Lloyd-Jones and Heidi M. Crane. “Assessing and Refining Myocardial Infarction Risk Estimation Among Patients With Human Immunodeficiency Virus: A Study by the Centers for AIDS Research Network of Integrated Clinical Systems”. JAMA Cardiology 2016 vol: 43 (1) pp: 27-34
DOI: 10.1001/jamacardio.2016.4494
Research funding: National Institutes of Health, American Heart Association.
Adapted from press release by Northwestern University.

Research finds potential cause of chronic inflammation in diabetic patients

Inflammation is one of the main reasons why people with diabetes experience heart attacks, strokes, kidney problems and other, related complications. Now, in a surprise finding, researchers at Washington University School of Medicine in St. Louis have identified a possible trigger of chronic inflammation. The study is available Nov. 2 as an advance online publication from the journal Nature.

Immune cells (shown in green) produce fatty acids that contribute
to diabetes-related inflammation. Credit: Semenkovich lab
Washington University School of Medicine

Semenkovich’s team made genetically altered mice that could not make the enzyme for fatty acid synthase (FAS) in immune cells called macrophages. Without the enzyme, it was impossible for the mice to synthesize fatty acids, a normal part of cell metabolism.

“We were surprised to find that the mice were protected from diet-induced diabetes,” said first author Xiaochao Wei, an instructor of medicine. “They did not develop the insulin resistance and diabetes that normally would have been induced by a high-fat diet.”

Through a series of experiments in the animals and in cell cultures, the researchers, including Douglas F. Covey, a professor of developmental biology and biochemistry, and Daniel S. Ory, MD, a professor of medicine and of cell biology and physiology, found that if macrophages could not synthesize fat from within, the external membranes of those cells could not respond to fat from outside the cells. That prevented the cells from contributing to inflammation.

But eliminating inflammation altogether is not the answer to preventing diabetic complications because inflammation is also vital for clearing infectious pathogens from the body and helps wounds heal. Still, Semenkovich said the new findings may have profound clinical implications.

“An inhibitor of fatty acid synthase actually is now in clinical trials as a potential cancer treatment,” he explained. “And other drugs have been developed to inhibit fatty acid synthase in diabetes, too. One possibility that our work suggests is that altering the lipid content in the cell membrane may help block cancer metastases and complications of diabetes.”

Drugs currently in use to block fatty acid synthase, as well as other developing strategies, potentially could allow for chronic inflammation to be blocked, without co
mpletely eliminating the ability of macrophages to fight infection. The researchers also plan to take a look at existing drug compounds that change the lipid composition in cells.

Citation:Wei X, Song H, Rizzo MG, Sidhu R, Covey DF, Ory DS, Semenkovich CF. Fatty acid synthesis configures the plasma membrane for inflammation in diabetes. Nature. Nov. 2, 2016.
DOI: http://dx.doi.org/10.1038/nature20117
Adapted from press release by Washington University School of Medicine

Transplantation with induced neural stem cells (iNSC) improves stroke recovery in mice

In a study to determine whether induced neural stem cells (iNSCs), a type of somatic cell directly differentiated into neural stem cells, could exert therapeutic effects when transplanted into mice modeled with ischemic stroke, researchers found that the cells promoted survival and functional recovery. Additionally, they discovered that when administered during the acute phase of stroke, iNSCs protected the brain from ischemia-related damage.

In contrast to other studies that have induced somatic cells to become pluripotent stem cells (iPSCs), which can then be differentiated into neural cells, this study directly converted somatic cells into neural stem cells. Researchers concluded that in addition to iNSC transplantation improving survival rate, results also demonstrated reduced infarct volume in the brain and enhanced sensorimotor function in the mice modeled with stroke. The study will be published in a future issue of Cell Transplantation.

“We observed multiple therapeutic effects when using these cells to treat stroke in mice,” said Dr. Koji Abe, Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science. “The iNSCs did not produce any adverse responses in the animals, including tumor formation, which may suggest they are safer than regular iPSCs. Further studies are needed to confirm this cell type as a candidate for cell replacement therapy for stroke.”

“Use of iNSCs may improve the efficacy of cell transplantation procedures for stroke since they are able to be derived directly from other cells without the need for extra steps,” said Dr. Shinn-Zong (John) Lin, Tzu Chi Hospital, Hualien City, Taiwan. “This is highly desirable in stroke, which has a narrow window in which the brain is most responsive to treatment. Whether the therapeutic effects produced by iNSCs are attributable to cell replacement or to secreted factors (paracrine effects), this method may be promising for treating stroke early.”

Publication: Novel therapeutic transplantation of induced neural stem cells for stroke.
DOI: http://dx.doi.org/10.3727/096368916X692988
Adapted from press release by Cell Transplantation

New MRI technique to assess stroke risk in atrial fibrillation patients by assessing blood velocity in heart

Affecting 33.5 million patients worldwide, atrial fibrillation is the most common form of cardiac arrhythmia. As if having an irregular heart beat wasn’t troubling enough, patients with atrial fibrillation are also much more likely to have a stroke.

Markl, who is a professor of biomedical engineering in Northwestern’s McCormick School of Engineering and of radiology in the Feinberg School of Medicine, has developed a new imaging technique that can help predict who is most at risk for stroke. This breakthrough could lead to better treatment and outcomes for patients with atrial fibrillation.

Supported by the American Heart Association and the National Institutes of Health, the research was described online this month in the journal Circulation: Cardiovascular Imaging.

Atrial fibrillation is linked to stroke because it slows the patient’s blood flow. The slow, sluggish blood flow can lead to blood clots, which can then travel to the brain and initiate stroke. Markl’s cardiac magnetic resonance (CMR) imaging test can detect the blood’s velocity through the heart and body. Called “atrial 4D flow CMR,” the technique is non-invasive and does not require contrast agents. The imaging program, which images blood flow dynamically and in the three spatial dimensions, comes in the form of software that can also be integrated into current MRI equipment without the need of special hardware and scanners or equipment upgrades.

“We simply programmed the scanner to generate information differently — in a way that wasn’t previously available,” Markl said. “It allows you to measure flow, diffusion of molecules, and tissue elasticity. You can interrogate the human body in a very detailed manner.”

Historically, physicians have attempted to assess stroke risk in atrial fibrillation patients by using a risk scoring system, which takes risk factors, such as age, general health, and gender, into account. Higher risk patients are then given medicine to prevent blood clots that lead to stroke.

“It’s very well accepted that these therapies significantly reduce the risk of stroke,” Markl said. “But they also increase risk of bleeding complications. It’s a dilemma that physicians face. They want to reduce one risk without introducing another risk. It’s particularly difficult for younger patients who might be on these medications for a long period of time. Maybe the risk of bleeding is initially small. But after taking medication for 20 or 30 years, it’s more and more likely that they’ll experience complications.”

4D flow imaging technique can give a more precise assessment of who needs the medication, preventing physicians from over treating their patients. In a pilot study with 60 patients and a control group, Markl found that atrial fibrillation patients who would have been considered high risk for stroke by the traditional scoring system in fact had normal blood flow, while patients who were considered lower risk sometimes had the slow blood flow indicative of potential clotting.

Publication: Left Atrial and Left Atrial Appendage 4D Blood Flow Dynamics in Atrial Fibrillation
DOI: 10.1161/CIRCIMAGING.116.004984
Adapted from press release by Northwestern University

Researchers find protein involved in death of brain cells during stroke

One particular protein is the final executioner of events that result in the death of brain cells during stroke, researchers from UT Southwestern Medical Center and their collaborators report. This finding could ultimately lead to new ways to protect against brain damage.

Researchers discovered that the protein, macrophage migration inhibitory factor (MIF), breaks the cell’s DNA, resulting in brain cell death.  “Stroke is a major cause of death and serious long-term disability in the world. The Centers for Disease Control and Prevention (CDC) estimates that annually more than 795,000 U.S. residents have a stroke,” said lead author Dr. Yingfei Wang, Assistant Professor of Pathology and of Neurology and Neurotherapeutics at UT Southwestern. The Department of Neurology and Neurotherapeutics is part of UT Southwestern’s Peter O’Donnell Jr. Brain Institute, a comprehensive initiative dedicated to better understanding the basic molecular workings of the brain and applying these discoveries to the prevention and treatment of brain diseases and injuries.

The study, which appears online in Science, outlines three possible ways to manipulate MIF to protect brain tissue during a stroke – and possibly in other brain-damaging conditions such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, although this study examined only stroke.
Dr. Wang screened thousands of human proteins to find 160 that could be the culprits behind stroke-induced cell death. Eventually, the researchers were able to narrow the field to just one – MIF, a protein long known for its roles in immunity and inflammation.  “The MIF protein was identified in the 1960s, but the function we found related to DNA damage in the cell’s nucleus after stroke is brand new,” Dr. Wang said.

The MIF finding is the final piece in a puzzle that collaborating researchers at Johns Hopkins University have been carefully assembling for years to reveal the process by which brain cells die.  This work was started in the labs of research partners Dr. Ted Dawson, Director of the Institute for Cell Engineering at the Johns Hopkins University School of Medicine, and Dr. Valina Dawson, Professor of Neurology at Johns Hopkins, where Dr. Wang began her work as a postdoctoral researcher and continued it as a collaboration between UT Southwestern and Johns Hopkins.

Despite their very different causes and symptoms, brain injury, stroke, and Alzheimer’s, Parkinson’s, and Huntington’s diseases have a shared mechanism involving a distinct form of “programmed” brain cell death called parthanatos, researchers said. The name comes from the personification of death in Greek mythology, and PARP, an enzyme involved in the cell death process.

“I can’t overemphasize what an important form of cell death it is; it plays a role in almost all forms of cellular injury,” said Dr. Dawson, whose research group has spent years delineating each of the links in the parthanatos chain of events and the roles of the proteins involved.  The researchers are working to identify chemical compounds that could block MIF’s actions and possibly protect brain cells from damage.

Adapted from press release by UT Southwestern