Experimental Drug Blocks Toxic Ion Flow Linked to Alzheimer’s Disease

An international team of researchers has shown that a new small-molecule drug can restore brain function and memory in a mouse model of Alzheimer’s disease. The drug works by stopping toxic ion flow in the brain that is known to trigger nerve cell death. Scientists envision that this drug could be used to treat Alzheimer’s and other neurodegenerative diseases such as Parkinson’s and ALS.

“This is the first drug molecule that can regulate memory loss by directly blocking ions from leaking through nerve cell membranes,” said Ratnesh Lal, a professor of bioengineering at the University of California San Diego and co-senior author of the study.

Various studies have linked Alzheimer’s disease to the accumulation of two particular proteins in the brain called amyloid-beta and tau. One theory is that these protein clusters create pores in nerve cell membranes that allow ions to travel in and out uncontrollably. This would alter ion levels inside the cells and in turn trigger neuronal dysfunction and cell death.

The new drug, a small molecule called anle138b, blocks these pores from moving ions in and out of nerve cells. Anle138b attaches to both amyloid-beta and tau protein clusters and deactivates the pores created by these clusters.

Researchers administered anle138b to mice with a genetic predisposition for developing an Alzheimer’s-like condition. The mice had symptoms such as abnormal brain function, impaired memory and high levels of either amyloid-beta or tau proteins in the brain. Treatment with anle138b normalized brain activity and improved learning ability in mice.

The study was led by the German Center for Neurodegenerative Diseases, the University Medical Center Göttingen, the Braunschweig University of Technology, the Max Planck Institute for Biophysical Chemistry, the Center for Nanoscale Microscopy and Molecular Physiology of the Brain in Göttingen, Germany, and the University of California San Diego. Researchers published their findings on Dec. 5 in EMBO Molecular Medicine.

Christian Griesinger, a professor at the Max Planck Institute for Biophysical Chemistry and co-senior author of the study, noted, “The drug is able to reach the brain when taken orally. Therefore, it is easy to administer, and we are currently performing toxicology studies to eventually be able to apply anle138b to humans.”

The team cautions that since the drug has so far only been tested in mice, it is unclear how well it would perform in humans. “I would like to emphasize that none of the current animal models fully recapitulate the symptoms seen in Alzheimer’s patients. Thus, care has to be taken when interpreting such data. However, our study offers evidence that anle138b has potential for neuroprotection,” said André Fischer, a senior researcher at the German Center for Neurodegenerative Diseases and the University Medical Center Göttingen, who is also a co-senior author of the study.

While collaborators in Germany will be pursuing clinical studies in human patients with neurodegenerative diseases, Lal and his research group at the UC San Diego Jacobs School of Engineering are particularly interested in testing anle138b on a variety of other diseases that are linked to toxic ion flow caused by amyloid proteins, including diabetes, tuberculosis and certain types of cancer. Lal’s group has performed extensive research on amyloid ion channels and their roles in these diseases. “Blocking the ion leakiness of amyloid channels using anle138b could be an effective therapy for various diseases,” Lal said.

Lal serves as co-director for the Center of Excellence for Nanomedicine and Engineering, a subcenter of the Institute of Engineering in Medicine at UC San Diego. His research group will also work on targeted delivery of the drug using their patent pending “nanobowls,” which are magnetically guided nanoparticles that can be packed with drugs and diagnostic molecules, deliver them to particular sites in the body and release them on demand. Future studies will focus on using these nanobowls to deliver anle138b to the brain, as well as other diseased tissues and organs affected by toxic amyloid-beta ion channels.

Potential New Autism Drug Shows Promise in Mice

Scientists have performed a successful test of a possible new drug in a mouse model of an autism disorder. The candidate drug, called NitroSynapsin, largely corrected electrical, behavioral and brain abnormalities in the mice.

NitroSynapsin is intended to restore an electrical signaling imbalance in the brain found in virtually all forms of autism spectrum disorder (ASD).

“This drug candidate is poised to go into clinical trials, and we think it might be effective against multiple forms of autism,” said senior investigator Stuart Lipton, M.D., Ph.D., Professor and Hannah and Eugene Step Chair at The Scripps Research Institute (TSRI), who is also a clinical neurologist caring for patients.

The research, published on today in the journal Nature Communications, was a collaboration involving scientists at the Scintillon Institute; the University of California, San Diego School of Medicine; Sanford Burnham Prebys Medical Discovery Institute and other institutions. Lipton’s fellow senior investigators on the project were Drs. Nobuki Nakanishi and Shichun Tu of the Scintillon Institute in San Diego.

ASD is brain development disorder that affects 1 in 68 children in the United States alone. Because ASD has been diagnosed more often in recent years, most Americans now living with autism diagnoses are children—roughly 2.4 percent of boys and 0.5 percent of girls.

Genetic Analysis Leads to Potential Treatment

The new study stemmed from a 1993 study in which Lipton and his laboratory, then at Harvard Medical School, identified a gene called MEF2C as a potentially important factor in brain development.

This breakthrough led Lipton and colleagues to the discovery that disrupting the mouse version of MEF2C in the brain, early in fetal development, causes mice to be born with severe, autism-like abnormalities. Since that discovery in mice in 2008, other researchers have reported many cases of children who have a very similar disorder, resulting from a mutation to one copy of MEF2C (human DNA normally contains two copies of every gene, one copy inherited from the father and one from the mother). The condition is now called MEF2C Haploinsufficiency Syndrome (MHS).

“This syndrome was discovered in people only because it was first discovered in mice—it’s a good example of why basic science is so important,” Lipton said.

MEF2C encodes a protein that works as a transcription factor, like a switch that turns on the expression of many genes. Although MHS accounts for only a small proportion of autism disorder cases, large-scale genomic studies in recent years have found that mutations underlying various autism disorders frequently involve genes whose activity is switched on by MEF2C.

“Because MEF2C is important in driving so many autism-linked genes, we’re hopeful that a treatment that works for this MEF2C-haploinsufficiency syndrome will also be effective against other forms of autism,” Lipton said, “and in fact we already have preliminary evidence for this.”

For the study, the researchers created a laboratory model of MHS by engineering mice to have—like human children with MHS—just one functioning copy of the mouse version of MEF2C, rather than the usual two copies. The mice showed impairments in spatial memory, abnormal anxiety and abnormal repetitive movements, plus other signs consistent with human MHS. Analyses of mouse brains revealed a host of problems, including an excess in key brain regions of excitatory signaling (which causes neurons to fire) over inhibitory signaling (which suppresses neuronal activity).

In short, these two important kinds of brain signals were out of balance. A similar excitatory/inhibitory (E/I) imbalance is seen in most forms of ASD and is thought to explain many of the core features of these disorders, including cognitive and behavioral problems and an increased chance of epileptic seizures.

The researchers treated the MHS-mice for three months with NitroSynapsin, an aminoadamantane nitrate compound related to the Alzheimer’s FDA-approved drug memantine, which was previously developed by Lipton’s group. NitroSynapsin is known to help reduce excess excitatory signaling in the brain, and the team found that the compound did reduce the E/I imbalance and also reduced abnormal behaviors in the mice and boosted their performance on cognitive/behavioral tests—in some cases restoring performance essentially to normal.

Lipton and colleagues are currently testing the drug in mouse models of other autism disorders, and they hope to move NitroSynapsin into clinical trials with a biotechnology partner.

The work also has support from parents of children with MHS. “We are all hanging on to the hope that one day our children will be able to speak, to understand and to live more independent lives,” said Michelle Dunlavy, who has a son with MHS.

In fact, Lipton’s group is also now using stem cell technology to create cell-based models of MHS with skin cells from children who have the syndrome—and NitroSynapsin appears to work in this ‘human context’ as well. Dunlavy and other parents of children with MHS recently organized an international, Facebook-based support group, which is coordinating to assist in Lipton’s research going forward.

In an amazing twist, the scientific team also found in Alzheimer’s disease models that the new NitroSynapsin compound improves synapse function, the specialized areas for communication between nerve cells. Thus, the ability of the drug to improve ‘network’ communication in the brain may eventually lead to its use in several neurological diseases.

Proton Therapy Lowers Treatment Side Effects in Pediatric Head and Neck Cancer Patients

Pediatric patients with head and neck cancer can be treated with proton beam therapy (PBT) instead of traditional photon radiation, and it will result in similar outcomes with less impact on quality of life. Researchers from the Perelman School of Medicine at the University of Pennsylvania as well as Children’s Hospital of Philadelphia analyzed cases of pediatric head and neck cancer treated with PBT between 2010 and 2016 and found similar rates of tumor control and lower rates of toxicity than what is historically expected from photon radiation. They published their findings today in the journal Pediatric Blood and Cancer.

Cancers of the head and neck account for about 12 percent of all pediatric cancers, and they are generally different tumor types than those that affect adults. For solid tumors like neuroblastoma, thyroid cancer, and soft tissue sarcomas, treatment usually involves a combination of therapies including chemotherapy, radiation, and surgery. Post-operative radiation can be critical, since surgeons may not be able to completely remove all cancer given the complexity of the head and neck region.

The area’s sensitivity also means the effects of treatment can lower patient quality of life due to symptoms including loss of appetite, difficulty swallowing, or mucositis – in which ulcers form in the digestive tract, usually in reaction to chemotherapy or radiation.

“These concerns are especially important to address in pediatric patients, since they’re still developing and may need to deal with any adverse effects for the rest of their lives. This study shows that protons may be an important tool in improving quality of life both during treatment and for years after for these young patients,” said the study’s senior author Christine Hill-Kayser, MD, chief of the Pediatric Radiation Oncology Service at Penn and an attending physician at CHOP. CHOP cancer patients who need radiation therapy are treated at Penn, including proton therapy through the Roberts Proton Therapy Center.

Jennifer Vogel, MD, a resident in Radiation Oncology at Penn, is the study’s lead author.

Researchers looked at 69 pediatric head and neck cancer patients treated with PBT at Penn and CHOP between 2010 and 2016. Thirty-five (50 percent) of those patients had rhabdomyosarcoma, a cancer of the cells that make up skeletal muscles. Ten (7 percent) were treated for Ewing sarcoma, a cancer most commonly found in the bone or soft tissue. The other 24 were treated for a variety of other cancers affecting the head and neck regions.

One year after treatment, 93 percent of patients were still alive, and 92 percent did not experience recurrence at their primary disease site.

Toxicities, or side effects, are measured on a scale from 1 to 5 with 5 being the most severe. In this study, no patients were above grade 3, and the most severe toxicities at that level were mucositis (4 percent), loss of appetite (22 percent), and difficulty swallowing (7 percent).

“Different disease sites required different dosage levels, and we specifically found the severity of muscositis was associated with higher doses of radiation,” Vogel said.

Those numbers are still well below what is typically associated with photon radiation. In rhabdomyosarcoma, for example, 46 percent of patients historically report grade 3 or 4 mucositis.

“These data show proton therapy is not only effective, it is also more tolerable for patients,” Hill-Kayser said. “This study shows this treatment is safe and offers practice guidelines for delivering head and neck proton therapy in the pediatric population.”

Researchers say they plan to follow up with these patients to evaluate long-term disease control and late-developing toxicity.

A Dietary Supplement Dampens the Brain Hyperexcitability Seen in Seizures or Epilepsy

Seizure disorders — including epilepsy — are associated with pathological hyperexcitability in brain neurons. Unfortunately, there are limited available treatments that can prevent this hyperexcitability. However, University of Alabama at Birmingham researchers have found that inducing a biochemical alteration in brain proteins via the dietary supplement glucosamine was able to rapidly dampen that pathological hyperexcitability in rat and mouse models.

These results represent a potentially novel therapeutic target for the treatment of seizure disorders, and they show the need to better understand the physiology underlying these neural and brain circuit changes.

Proteins are the workhorses of living cells, and their activities are tightly and rapidly regulated in responses to changing conditions. Adding or removing a phosphoryl group to proteins is a well-known regulator for many proteins, and it is estimated that human proteins may have as many as 230,000 sites for phosphorylation.

A lesser-known regulation comes from the addition or removal of N-acetylglucosamine to proteins, which is usually controlled by glucose, the primary fuel for neurons. Several years ago, neuroscientist Lori McMahon, Ph.D., professor of cell, developmental and integrative biology at UAB, found out from her colleague John Chatham, D.Phil., a UAB professor of pathology and a cardiac physiologist, that brain cells had the second-highest amounts of proteins with N-acetylglucosamine, or O-GlcNAcylation, in the body.

At the time, very little was known about how O-GlcNAcylation might affect brain function, so McMahon and Chatham started working together. In 2014, McMahon and Chatham, in a study led by graduate student Erica Taylor and colleagues, reported that acute increases in protein O-GlcNAcylation caused long-term synaptic depression, a reduction in neuronal synaptic strength, in the hippocampus of the brain. This was the first time acute changes in O-GlcNAcylation of neuronal proteins were shown to directly change synaptic function.

Since neural excitability in the hippocampus is a key feature of seizures and epilepsy, they hypothesized that acutely increasing protein O-GlcNAcylation might dampen the pathological hyperexcitability associated with these brain disorders.

That turned out to be the case, as reported in the Journal of Neuroscience study, “Acute increases in protein O-GlcNAcylation dampen epileptiform activity in hippocampus.” The study was led by corresponding author McMahon and first author Luke Stewart, a doctoral student in the Neuroscience Theme of the Graduate Biomedical Sciences Program. Stewart is co-mentored by McMahon and Chatham.

“Our findings support the conclusion that protein O-GlcNAcylation is a regulator of neuronal excitability, and it represents a promising target for further research on seizure disorder therapeutics,” they wrote in their research significance statement. The researchers caution that the mechanism underlying the dampening is likely to be complex.

Research details
Glucose, the major fuel for neurons, also controls the levels of protein O-GlcNAcylation on proteins. However, high levels of the dietary supplement glucosamine, or an inhibitor of the enzyme that removes O-GlcNAcylation, leads to rapid increases in O-GlcNAc levels.

In experiments with hippocampal brain slices treated to induce a stable and ongoing hyperexcitability, UAB researchers found that an acute increase in protein O-GlcNAcylation significantly decreased the sudden bursts of electrical activity known as epileptiform activity in area CA1 of the hippocampus. An increased protein O-GlcNAcylation in normal cells also protected against a later induction of drug-induced hyperexcitability.

The effects were seen in slices treated with both glucosamine and an inhibitor of the enzyme that removes O-GlcNAc groups. They also found that treatment with glucosamine alone for as short a time as 10 minutes was able to dampen ongoing drug-induced hyperexcitability.

In common with the long-term synaptic depression provoked by increased O-GlcNAcylation, the dampening of hyperexcitability required the GluA2 subunit of the AMPA receptor, which is a glutamate-gated ion channel responsible for fast synaptic transmission in the brain. This finding suggested a conserved mechanism for the two changes provoked by increased O-GlcNAcylation — synaptic depression and dampening of hyperexcitability.

The researchers also found that the spontaneous firing of pyramidal neurons in another region of hippocampus, area CA3, was reduced by increased O-GlcNAcylation in normal brain slices and in slices with drug-induced hyperexcitability. This reduction in spontaneous firing of CA3 pyramidal neurons likely contributes to decreased hyperexcitability in area CA1 since the CA3 neurons directly excite those in CA1.

Similar to the findings for brain slices, mice that were treated to increase O-GlcNAcylation before getting drug-induced hyperexcitability had fewer of the brain activity spikes associated with epilepsy that are called interictal spikes. Several drug-induced hyperexcitable mice had convulsive seizures during the experiments — this occurred in both the increased O-GlcNAcylation mice and the control mice. Brain activity during the seizures differed between these two groups: The peak power of the brain activity for the mice with increased O-GlcNAcylation occurred at a lower frequency, as compared with the control mice.

Cell Surface Protein May Offer Big Target in Treating High-Risk Childhood Cancers

Oncology researchers studying high-risk children’s cancers have identified a protein that offers a likely target for immunotherapy–harnessing the immune system in medical treatments. In cell cultures and animal models, a potent drug attached to an antibody selectively zeroes in on cancer cells without harming healthy cells.

“We have built a strong foundation for developing a completely new and hopefully much less toxic treatment for neuroblastoma, the most common cancer in infants,” said study supervisor John M. Maris, MD, a pediatric oncologist at Children’s Hospital of Philadelphia (CHOP). “Furthermore, our findings may also lend support to the development of other immune-based therapies, such as CAR T-cells, in children with multiple aggressive cancers in addition to neuroblastoma.”

Maris, along with study leader and first author Kristopher R. Bosse, MD, and colleagues published their study today in Cancer Cell, which featured their findings as the cover story.

Neuroblastoma is a cancer of the developing peripheral nervous system that usually occurs as a solid tumor in a child’s chest or abdomen, and is the most common cancer in infants. It accounts for a disproportionate share of cancer deaths in children. Over decades, CHOP clinicians and researchers have built one of the world’s leading programs in neuroblastoma.

The study team used sophisticated sequencing tools to first discover molecules that are much more commonly found on the surface of neuroblastoma cells than on normal cells. “Our rationale was to identify a cell-surface molecule that an immune-based therapy could target without damaging healthy tissues,” said Bosse. “Using this approach, we identified a protein called glypican-2, or GPC2.” GPC2 is one of a family of glypicans—cell-surface proteins that interact with growth factors and cell surface receptors, influencing many intracellular signaling pathways important in development and cancer.

In addition to GPC2’s presence on neuroblastoma cells, the study team also found that GPC2 is necessary for a neuroblastoma tumor to proliferate. Both of those facts implied that a compound that acted against GPC2 might kill cancer cells, spare healthy cells, and limit the possibility of these tumors developing “immune escape” mechanisms, in which cancer cells resist an immunotherapy by shedding the target. “Given GPC2’s critical role in the growth of neuroblastomas, we hope that tumors will not be able to simply downregulate this protein in order to escape recognition by our immunotherapies that target GPC2,” said Bosse.

After pinpointing GPC2 as a very promising target for therapy, the researchers next worked with their colleagues at the National Cancer Institute to search for a weapon. They developed an antibody-drug conjugate (ADC) called D3-GPC2-PBD, which combined a very specific antibody that recognizes GPC2 with a potent chemotherapy drug that is internalized specifically by cancer cells. The drug payload damages DNA in tumors, while sparing healthy tissues from its toxic effects.

In cell cultures and mouse models of neuroblastoma, the ADC robustly killed neuroblastoma cells with no discernible toxicity to normal cells. “These findings establish that this type of immunotherapy could be potentially safe and effective against neuroblastoma,” said Maris. “Our next steps will be to further evaluate this ADC and also develop other immune-based therapies directed against GPC2. Because other glypicans in addition to GPC2 are overexpressed in other childhood cancers, it may also be possible to apply this approach across various types of high-risk pediatric cancers.”

Researchers Find a Potential Target for Anti-Alzheimer’s Treatments

Scientists at the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg have identified a gene that may provide a new starting point for developing treatments for Alzheimer’s disease (AD). The USP9 gene has an indirect influence on the so-called tau protein, which is believed to play a significant role in the onset of Alzheimer’s disease. This discovery by the LCSB researchers, led by Dr. Enrico Glaab, may open a new door to developing active ingredients to treat Alzheimer’s disease. The scientists recently published their findings in the journal Molecular Neurobiology (DOI: 10.1007/s12035-016-0299-z).

Alzheimer’s disease is characterised by the progressive destruction of brain cells and their contacts (neurons and synapses). The brains of Alzheimer patients exhibit protein deposits known as amyloid plaques. The symptoms of the disease are memory disorders, disorientation, speech impediments, impaired thinking and judgement, and even personality changes. The likelihood of developing AD increases dramatically with age. The number of people affected is therefore rising along with our increasing life expectancy: An estimated 35 million people in the world have Alzheimer’s disease today. By 2030, this number could rise to about 65 million, and by 2050 to over 100 million. It has never been fully explained how the disease develops. It is likely, however, that molecular malformations in brain cells play a crucial role, involving among other molecules the so-called tau proteins. In Alzheimer’s patients, tau proteins aggregate into tangles of threadlike structures, called neurofibrils, which deposit between the brain cells and disrupt their function.

“The risk of developing Alzheimer’s disease at an advanced age is much higher in women than in men – even after adjusting for the longer average life expectancy of women,” says Dr. Enrico Glaab, head of the research group Biomedical Data Science at LCSB. Glaab took this as a hint to start looking for molecular differences between the sexes that could contribute to the differences in frequency and characteristics of the disease. To do so, he and his team analysed thousands of data series on samples from the brains of around 650 deceased people of both sexes, some of whom had been afflicted with the disease and others who had not.

The researchers encountered a gene that could be an important determinant for the gender-specific differences in Alzheimer’s disease pathology. The gene, called ubiquitin-specific peptidase 9 (USP9), influences the activity of another gene that encodes the microtubule associated protein tau (MAPT). MAPT, in turn, is already suspected of being heavily involved in the onset of Alzheimer’s disease.

To study the action of USP9, and the relationship between its role and the role of tau in Alzheimer’s disease, Enrico Glaab and colleagues from other LCSB workgroups examined the gene in cell cultures and zebrafish experiments. The scientists blocked the activity of USP9 and measured the effects of this “knockdown” on MAPT gene activity in the two model systems of cell cultures and zebrafish.

“We were able to show that USP9 knockdown significantly reduces the activity of the tau gene in both models,” Glaab reports. Accordingly, USP9 could serve as a target for future tau-modulating small molecule compounds – even if there is still a long way to go before anti-Alzheimer’s drugs based on this principle can be developed.

To gain a deeper understanding of the molecular signal chain connecting USP9 and MAPT, the researchers at LCSB developed a computer model that combines the measured data with known regulatory information from the literature. They discovered that proteins that had already been suggested as potential drug targets are also influenced by USP9. Through parallel alteration of multiple tau regulators, USP9 could therefore have a greater effect as a pharmaceutical target than previously proposed targets.

New Hope For Recovery Of Hand Movement For Stroke Patients

Stroke patients are starting a trial of a new electronic device to recover movement and control of their hand.

Neuroscientists at Newcastle University have developed the device, the size of a mobile phone, which delivers a series of small electrical shocks followed by an audible click to strengthen brain and spinal connections.

The experts believe this could revolutionise treatment for patients, providing a wearable solution to the effects of stroke.

Following successful work in primates and healthy human subjects, the Newcastle University team are now working with colleagues at the prestigious Institute of Neurosciences, Kolkata, India, to start the clinical trial. Involving 150 stroke patients, the aim of the study is to see whether it leads to improved hand and arm control.

Stuart Baker, Professor of Movement Neuroscience at Newcastle University who has led the work said: “We were astonished to find that a small electric shock and the sound of a click had the potential to change the brain’s connections. However, our previous research in primates changed our thinking about how we could activate these pathways, leading to our study in humans.”

Recovering hand control

Publishing today in the Journal of Neuroscience, the team report on the development of the miniaturised device and its success in healthy patients at strengthening connections in the reticulospinal tract, one of the signal pathways between the brain and spinal cord.

This is important for patients as when people have a stroke they often lose the major pathway found in all mammals connecting the brain to spinal cord. The team’s previous work in primates showed that after a stroke they can adapt and use a different, more primitive pathway, the reticulospinal tract, to recover.

However, their recovery tends to be imbalanced with more connections made to flexors, the muscles that close the hand, than extensors, those that open the hand. This imbalance is also seen in stroke patients as typically, even after a period of recuperation, they find that they still have weakness of the extensor muscles preventing them opening their fist which leads to the distinctive curled hand.

Partial paralysis of the arms, typically on just one side, is common after stroke, and can affect someone’s ability to wash, dress or feed themselves. Only about 15% of stroke patients spontaneously recover the use of their hand and arm, with many people left facing the rest of their lives with a severe level of disability.

Senior author of the paper, Professor Baker added: “We have developed a miniaturised device which delivers an audible click followed by a weak electric shock to the arm muscle to strengthen the brain’s connections. This means the stroke patients in the trial are wearing an earpiece and a pad on the arm, each linked by wires to the device so that the click and shock can be continually delivered to them.

“We think that if they wear this for 4 hours a day we will be able to see a permanent improvement in their extensor muscle connections which will help them gain control on their hand.”

Improving connections

The techniques to strengthen brain connections using paired stimuli are well documented, but until now this has needed bulky equipment, with a mains electric supply.

The research published today is a proof of concept in human subjects and comes directly out of the team’s work on primates. In the paper they report how they pair a click in a headphone with an electric shock to a muscle to induce the changes in connections either strengthening or weakening reflexes depending on the sequence selected. They demonstrated that wearing the portable electronic device for seven hours strengthened the signal pathway in more than half of the subjects (15 out of 25).

Professor Stuart Baker added: “We would never have thought of using audible clicks unless we had the recordings from primates to show us that this might work. Furthermore, it is our earlier work in primates which shows that the connections we are changing are definitely involved in stroke recovery.”

The work has been funded through a Milstein Award from the Medical Research Council and the Wellcome Trust.

The clinical trial is just starting at the Institute of Neurosciences, Kolkata, India. The country has a higher rate of stroke than Western countries which can affect people at a younger age meaning there is a large number of patients. The Institute has strong collaborative links with Newcastle University enabling a carefully controlled clinical trial with results expected at the end of this year.

Brain Cancer And Leukemia: New Molecular Mechanisms Decoded

Brain cancer and leukemia are two potentially fatal diseases that affect thousands of Canadians each year. But a joint study conducted by researchers Frederick Antoine Mallette, of the Maisonneuve-Rosemont Hospital Research Centre and the University of Montreal, and Marc-Étienne Huot, of Laval University, and published in the prestigious scientific journal Nature Communications has uncovered new molecular causes of brain cancer and leukemia.

We already knew the existence of a mutation phenomenon involving certain metabolic enzymes called isocitrate dehydrogenases 1 and 2 (IDH1/2) in various forms of brain cancer, including gliomas and glioblastomas, and in acute myeloid leukemia. Although the mutated forms of IDH1/2 appear to contribute to cancer formation, until now we had only limited understanding of the ways in which these metabolic defects caused cancer. Research conducted by Mélissa Carbonneau, a master’s student in Professor Mallette’s laboratory, has helped to better understand the effect of IDH1/2 mutations in cancer by demonstrating their role in activating the pathways involved in cell proliferation and survival.

“With the identification of the molecular modes of action that contribute to cancer in patients carrying IDH1/2 mutations, it is now possible to consider personalized treatment to potentially improve therapeutic response,” said Dr. Mallette.
Some statistics

It is estimated that in 2015, 3,000 Canadians were diagnosed with brain and spinal cord cancer, and 6,200 Canadians were diagnosed with leukemia.

Stereotactic Radiosurgery May Be Best for Patients with Metastatic Brain Tumors

Patients with three or fewer metastatic brain tumors who received treatment with stereotactic radiosurgery (SRS) had less cognitive deterioration three months after treatment than patients who received SRS combined with whole brain radiation therapy (WBRT). These findings are according to the results of a federally funded, Mayo Clinic-led, multi-institution research study published today in the Journal of the American Medical Association.

“Metastatic brain tumors are unfortunately common in patients with cancer,” says Paul Brown, M.D., a radiation oncologist at Mayo Clinic and the lead author of the study. Dr. Brown says that, while SRS gives physicians the opportunity to treat tumors and spare healthy brain tissue, a combination of SRS plus WBRT has been shown to help control growth of metastatic brain tumors. “The concern is that WBRT also damages cognitive function,” says Dr. Brown. “That is why we have been studying the use of SRS alone.”

Researchers enrolled 213 patients between February 2002 and December 2013, and randomly assigned them to treatment with SRS alone (111) or SRS followed by WBRT (102). Researchers found less cognitive deterioration at three months in patients treated with SRS alone. Quality of life (QOL) was also higher at three months among patients treated with SRS alone. There was no significant difference in functional independence at three months between treatment groups. Median overall survival was 10.4 months for patients treated with SRS alone and 7.4 months for patients treated with SRS and WBRT.

“This is the first large-scale clinical trial to evaluate this patient population with a comprehensive battery of cognitive and QOL instruments,” Dr. Brown says. “WBRT has often been offered early in the disease course for patients with metastatic brain tumors, but, because of this trial, we know the negative impact of WBRT on both quality of life and cognitive function is significant. With these trial findings, we expect practice will shift, reserving WBRT for patients with more extensive disease in the brain.”

International Study Finds Effective, Less Toxic Way to Treat Brain Tumors

Physicians from Carolinas HealthCare System’s Neurosciences Institute and Levine Cancer Institute are among the authors of a study that was accepted for publication by the Journal of the American Medical Association (JAMA). The study, released on July 26, 2016, shows that patients with the most common form of brain tumor can be treated in an effective and substantially less toxic way by omitting a widely used portion of radiation therapy. These results will allow tens of thousands of patients with brain tumors to experience a better quality of life while maintaining the same length of life.

Anthony L. Asher, MD, FACS, medical director at Carolinas HealthCare System’s Neurosciences Institute and the senior author on the report, and as well as Stuart H. Burri, MD, chairman, department of radiation oncology at Levine Cancer Institute, began their research on this subject over 10 years ago in Charlotte, North Carolina. Along with Dr. Paul Brown at Mayo Clinic, they spearheaded an international, multi-institutional, randomized trial that will ultimately improve the standard of care for patients with a specific type of brain tumor, brain metastases, by reducing the toxicity of their treatment without reducing the effectiveness.

Typical therapies for these types of brain tumors include surgery, whole brain radiation therapy and focused radiation, also known as stereotactic radiosurgery. “We discovered that whole brain radiation added to focused radiation in the treatment of brain metastases – in other words, cancer that travels to the brain- reduces the number of new brain tumors over time; however, patients receiving the whole brain radiation had significantly more difficulties with memory and complex thinking than patients who only had the focused radiation,” says Dr. Asher.

“Whole brain radiation patients also reported worse quality of life compared with patients who only received the focused radiation,” adds Dr. Burri. “Interestingly, the data showed that the addition of whole brain radiation produced no improvement in survival.”

According to the American Cancer Society, in 2016, there will be approximately 1.7 million new cancer cases diagnosed in the United States. Almost one in four of those patients (about 400,000) will experience spread of their cancers to the brain. In contrast, 300,000 and 240,000 patients will be newly diagnosed with breast and primary lung cancers, respectively, each year. “Brain metastases are not only extremely common, they are also a major source of disability in society,” says Dr. Asher. Because of their location, these tumors often produce severe neurological symptoms, such as headaches, weakness or problems with speech and information processing, thereby compromising both daily function and quality of life in cancer patients.

According to Dr. Asher, there are two primary objectives in cancer care:

To improve survival
To maintain or improve quality of life for patients
“The first and highest rule of medical care is ‘do no harm,'” says Dr. Asher. “Consistent with that obligation, when it isn’t possible to extend survival with various therapies, it’s absolutely essential that we work to reduce or eliminate any possibility that quality of life will be compromised by treatments. Another way to state that principle for cancer care, is that when two cancer therapies produce similar survival, it’s important to understand which therapy offers patients a better quality of life.”

In this study, although whole brain radiation decreased the number of new brain tumors over time, its addition to focused radiation interestingly did not result in a survival benefit over focused radiation alone. Furthermore, whole brain therapy was associated with considerably worse quality of life.

“In the past, clinicians who treated patients with brain tumors seldom used sophisticated techniques like neurocognitive tests to evaluate patients’ daily function in response to various therapies,” said Dr. Burri. “Without those tests, we might have incorrectly concluded that whole brain radiation was a better option for patients because it made their scans look better, at least in the short term. However, the data from our study shows that clinicians can no longer simply rely on the results of traditional lab tests or scans to assess the value of care; we have to understand the total impact of cancer therapies on our patients.”

Drs. Asher and Burri emphasize that the real importance of this study is its potential to make us think differently about what really matters in cancer therapy.

The trial authors concluded that the benefit of adding whole brain radiation was outweighed by its risks in patients with one to three newly diagnosed brain metastases. This is a very relevant finding, as over 200,000 patients still receive whole brain radiation in the United States each year, and the majority of patients with brain metastases have a limited number (typically three or less) of brain lesions. Drs. Asher and Burri, along with their co-investigators, now recommend that patients with one to three brain metastases should no longer receive routine whole brain radiation therapy, and should be treated with focused therapy alone to better preserve cognitive function and quality of life.

“Having the research published in JAMA is validation of more than a decade of work,” says Dr. Burri. ” It is deeply satisfying to have developed an important scientific project, work in close collaboration with other investigators to obtain support from the National Cancer Institute, then carry the to carry the trial to completion with publication of impactful results in one of the leading medical journals in the world.”

Drs. Asher and Burri are now working on a new method of focused therapy for tumors that have spread to the brain that combines radiation and surgery. The technique was pioneered at Levine Cancer Institute and they are looking to expand and further validate the approach with the National Cancer Institute.

Antibiotics Weaken Alzheimer’s Disease Progression Through Changes in the Gut Microbiome

Long-term treatment with broad spectrum antibiotics decreased levels of amyloid plaques, a hallmark of Alzheimer’s disease, and activated inflammatory microglial cells in the brains of mice in a new study by neuroscientists from the University of Chicago.

The study, published July 21, 2016, in Scientific Reports, also showed significant changes in the gut microbiome after antibiotic treatment, suggesting the composition and diversity of bacteria in the gut play an important role in regulating immune system activity that impacts progression of Alzheimer’s disease.

“We’re exploring very new territory in how the gut influences brain health,” said Sangram Sisodia, PhD, Thomas Reynolds Sr. Family Professor of Neurosciences at the University of Chicago and senior author of the study. “This is an area that people who work with neurodegenerative diseases are going to be increasingly interested in, because it could have an influence down the road on treatments.”

Two of the key features of Alzheimer’s disease are the development of amyloidosis, accumulation of amyloid-ß (Aß) peptides in the brain, and inflammation of the microglia, brain cells that perform immune system functions in the central nervous system. Buildup of Aß into plaques plays a central role in the onset of Alzheimer’s, while the severity of neuro-inflammation is believed to influence the rate of cognitive decline from the disease.

For this study, Sisodia and his team administered high doses of broad-spectrum antibiotics to mice over five to six months. At the end of this period, genetic analysis of gut bacteria from the antibiotic-treated mice showed that while the total mass of microbes present was roughly the same as in controls, the diversity of the community changed dramatically. The antibiotic-treated mice also showed more than a two-fold decrease in Aß plaques compared to controls, and a significant elevation in the inflammatory state of microglia in the brain. Levels of important signaling chemicals circulating in the blood were also elevated in the treated mice.

While the mechanisms linking these changes is unclear, the study points to the potential in further research on the gut microbiome’s influence on the brain and nervous system.

“We don’t propose that a long-term course of antibiotics is going to be a treatment—that’s just absurd for a whole number of reasons,” said Myles Minter, PhD, a postdoctoral scholar in the Department of Neurobiology at UChicago and lead author of the study. “But what this study does is allow us to explore further, now that we’re clearly changing the gut microbial population and have new bugs that are more prevalent in mice with altered amyloid deposition after antibiotics.”

The study is the result of one the first collaborations from the Microbiome Center, a joint effort by the University of Chicago, the Marine Biological Laboratory and Argonne National Laboratory to support scientists at all three institutions who are developing new applications and tools to understand and harness the capabilities of microbial systems across different fields. Sisodia, Minter and their team worked with Eugene B. Chang, Martin Boyer Professor of Medicine at UChicago, and Vanessa Leone, PhD, a postdoctoral scholar in Chang’s lab, to analyze the gut microbes of the mice in this study.

Minter said the collaboration was enabling, and highlighted the cross-disciplinary thinking necessary to tackle a seemingly intractable disease like Alzheimer’s. “Once you put ideas together from different fields that have largely long been believed to be segregated from one another, the possibilities are really amazing,” he said.

Sisodia cautioned that while the current study opens new possibilities for understanding the role of the gut microbiome in Alzheimer’s disease, it’s just a beginning step.

“There’s probably not going to be a cure for Alzheimer’s disease for several generations, because we know there are changes occurring in the brain and central nervous system 15 to 20 years before clinical onset,” he said. “We have to find ways to intervene when a patient starts showing clinical signs, and if we learn how changes in gut bacteria affect onset or progression, or how the molecules they produce interact with the nervous system, we could use that to create a new kind of personalized medicine.”

Changes Uncovered in the Gut Bacteria of Patients with Multiple Sclerosis

A connection between the bacteria living in the gut and immunological disorders such as multiple sclerosis have long been suspected, but for the first time, researchers have detected clear evidence of changes that tie the two together. Investigators from Brigham and Women’s Hospital (BWH) have found that people with multiple sclerosis have different patterns of gut microorganisms than those of their healthy counterparts. In addition, patients receiving treatment for MS have different patterns than untreated patients. The new research supports recent studies linking immunological disorders to the gut microbiome and may have implications for pursuing new therapies for MS.

“Our findings raise the possibility that by affecting the gut microbiome, one could come up with treatments for MS – treatments that affect the microbiome, and, in turn, the immune response,” said Howard L. Weiner, MD, director of the Partners MS Center and co-director of the Ann Romney Center for Neurologic Disease at Brigham Women’s Hospital, . “There are a number of ways that the microbiome could play a role in MS and this opens up a whole new world of looking at the disease in a way that it’s never been looked at before.”

Weiner and colleagues conducted their investigations using data and samples from subjects who are part of the CLIMB (Comprehensive Longitudinal Investigation of Multiple Sclerosis) study at Brigham and Women’s Hospital. The team analyzed stool samples from 60 people with MS and 43 control subjects, performing gene sequencing to detect differences in the microbial communities of the subjects.

Samples from MS patients contained higher levels of certain bacterial species – including Methanobrevibacter and Akkermansia – and lower levels of others – such as Butyricimonas – when compared to healthy samples. Other studies have found that several of these microorganisms may drive inflammation or are associated with autoimmunity. Importantly, the team also found that microbial changes in the gut correlated with changes in the activity of genes that play a role in the immune system. The team also collected breath samples from subjects, finding that, as a result of increased levels of Methanobrevibacter, patients with MS had higher levels of methane in their breath samples.

The researchers also investigated the gut microbe communities of untreated MS patients, finding that MS disease-modifying therapy appeared to normalize the gut microbiomes of MS patients. The researchers note that further study will be required to determine the exact role that these microbes may be playing in the progression of disease and whether or not modifying the microbiome may be helpful in treating MS. They plan to continue to explore the connection between the gut and the immune system in a larger group of patients and follow changes over time to better understand disease progression and interventions.

“This work provides a window into how the gut can affect the immune system which can then affect the brain,” said Weiner, who is also a professor of Neurology at Harvard Medical School. “Characterizing the gut microbiome in those with MS may provide new opportunities to diagnose MS and point us toward new interventions to help prevent disease development in those who are at risk.”

Understanding How Chemical Changes in the Brain Affect Alzheimer’s Disease

A new study from Western University is helping to explain why the long-term use of common anticholinergic drugs used to treat conditions like allergies and overactive bladder lead to an increased risk of developing dementia later in life. The findings show that long-term suppression of the neurotransmitter acetylcholine – a target for anticholinergic drugs – results in dementia-like changes in the brain.

“There have been several epidemiological studies showing that people who use these drugs for a long period of time increase their risk of developing dementia,” said Marco Prado, PhD, a Scientist at the Robarts Research Institute and Professor in the departments of Physiology and Pharmacology and Anatomy & Cell Biology at Western’s Schulich School of Medicine & Dentistry. “So the question we asked is ‘why?'”

For this study, published in the journal Cerebral Cortex, the researchers used genetically modified mouse models to block acetylcholine in order to mimic the action of the drugs in the brain. Neurons that use acetylcholine are known to be affected in Alzheimer’s disease; and the researchers were able to show a causal relationship between blocking acetylcholine and Alzheimer’s-like pathology in mice.

“We hope that by understanding what is happening in the brain due to the loss of acetylcholine, we might be able to find new ways to decrease Alzheimer’s pathology,” said Prado.

Prado and his partner Dr. Vania Prado, DDS, PhD, along with PhD candidates Ben Kolisnyk and Mohammed Al-Onaizi, have shown that blocking acetylcholine-mediated signals in neurons causes a change in approximately 10 per cent of the Messenger RNAs in a region of the brain responsible for declarative memory. Messenger RNA encodes for specific amino acids which are the building blocks for proteins and several of the changes they uncovered in the brains of mutant mice are similar to those observed in Alzheimer’s disease.

“We demonstrated that in order to keep neurons healthy you need acetylcholine,” said Prado. “So if acetylcholine actions are suppressed, brain cells respond by drastically changing their messenger RNAs and when they age, they show signs of pathology that have many of the hallmarks of Alzheimer’s disease.” Importantly, by targeting one of the messenger RNA pathways they uncovered, the researchers improved pathology in the mutant mice.

The study, conducted at Western’s Robarts Research Institute, used human tissue samples to validate the mouse data and mouse models to show not only the physical changes in the brain, but also behavioral and memory changes. The researchers were able to show that long-term suppression of acetylcholine caused brain cell to die and as a consequence decrease memory in the aging mice.

“When the mutant mice were old, memory tasks they mastered at young age were almost impossible for them, whereas normal mice still performed well,” said Kolisnyk.

The researchers hope their findings will have an impact on reducing the burden of dementia by providing new ways to reverse the loss of acetylcholine.

Case Western Reserve University Receives NIH Funding to Participate in Launch of Genomics Center on Alzheimer’s Disease

Case Western Reserve University School of Medicine is one of six recipients of a five-year, $10.8 million award from the National Institute on Aging, part of the National Institutes of Health, to establish the Coordinating Center for Genetics and Genomics of Alzheimer’s disease.

The hope is that discovering genetic risk and prevention factors will enable and accelerate development of prevention and treatments.

The project is a joint venture of researchers from the Perelman School of Medicine at the University of Pennsylvania in Philadelphia and five other institutions, including Case Western Reserve. The other four sites are Boston University, Columbia University, the University of Miami, and the Indiana University. It is part of the NIH Alzheimer’s Disease Sequencing Project, a project involving the same six institutions that began in 2012.

The Coordinating Center for Genetics and Genomics of Alzheimer’s disease will include genomic sequence data from thousands of people with Alzheimer’s disease as well as older cognitively normal subjects. Genome sequencing entails mapping out the order of chemical letters in a cell’s DNA. The goal is to identify genes that contribute to or help guard against Alzheimer’s disease. This work is done using highly sophisticated technology and statistical analysis.

“Understanding Alzheimer’s disease requires massive amounts of data,” said Jonathan Haines, PhD, chair of the department of epidemiology and biostatistics, and director of the Institute for Computational Biology at Case Western Reserve University School of Medicine, where much of the data analysis will occur. “By enabling us to create a common database to which potentially hundreds of researchers will have access, this funding will allow critical sharing of information and interpretation, which is essential for making progress against this insidious disease.”

William S. Bush, PhD, assistant professor of epidemiology and biostatistics at the School of Medicine, is participating in the project as well.

Haines and Bush will use their analytical and biomedical informatics expertise in this project in two ways. First, they will analyze the possible effects of multiple genes in helping cause or prevent Alzheimer’s. Second, they will provide guidance in connecting and interpreting the Alzheimer’s data with data from over 30 different databases of biological knowledge. This includes looking at correlations between the Alzheimer’s data and genes for: 1) other traits and medical conditions and 2) more basic biological mechanisms, such as determining if possible Alzheimer’s-related genes are even expressed — active — in the brain. “Placing our new statistical findings within the current understanding of Alzheimer’s disease biology is essential to move towards new therapies and preventions,” said Bush.

The Alzheimer’s Association defines Alzheimer’s as “a type of dementia that causes problems with memory, thinking and behavior. Symptoms usually develop slowly and get worse over time, becoming severe enough to interfere with daily tasks.” It affects as many as five million people age 65 and older in the United States.

Current drugs are only minimally effective in reducing the severity and progression of the disease. There are no known ways to prevent Alzheimer’s disease.

The new center comprises a major part of the NIH’s National Plan to Address Alzheimer’s Disease to prevent and effectively treat Alzheimer’s disease by 2025.

Penn Medicine Team and Collaborators Receive NIH Award to Launch Genomics Center on Alzheimer’s Disease

A five-year, projected $10.8 million award from the National Institute on Aging (NIA), part of the National Institutes of Health (NIH), will establish the Coordinating Center for Genetics and Genomics of Alzheimer’s Disease, a joint venture of researchers from the Perelman School of Medicine at the University of Pennsylvania and five other institutions. Penn will receive an estimated $4.5 million from the grant.

The Center is led by Gerard D. Schellenberg, PhD, a professor of Pathology and Laboratory Medicine and Li-San Wang, PhD, an associate professor of Pathology and Laboratory Medicine, in partnership with investigators from five other sites — Boston University, Case Western Reserve University, Columbia University, the University of Miami, and the University of Indiana.
“By coordinating the identification of Alzheimer’s-related genes, the Center’s team aims to find new therapeutic targets to reduce the economic and human burden caused by this disease,” Schellenberg said. “This is an exciting opportunity to apply new technologies to improve our understanding of the biological pathways underlying this devastating disease. The new center will stimulate collaborations between hundreds of U.S. and international Alzheimer’s genetics researchers by aggregating and analyzing very large data sets and sharing the results. This type of global interaction is needed if we are to make progress in solving this devastating illness.”

Alzheimer’s disease, a progressive neurodegenerative disorder, has become an epidemic that currently affects as many as five million people age 65 and older in the United States, with economic costs that are comparable to, if not greater than, caring for those of heart disease or cancer. Available drugs only marginally affect disease severity and progression. While there is no way to prevent this disease, the discovery of genetic risk factors for Alzheimer’s is bringing researchers closer to learning how the genes work together and may help identify the most effective interventions.
“The Genomics Center will be a state-of-the-art national clearinghouse for Alzheimer’s genomics information based at Penn,” Wang said. “We have an important mission to move the field of Alzheimer’s genetics forward by coordinating all NIA-funded activities for the Alzheimer’s Disease Sequencing Project.”

Center collaborators will collect and “harmonize” available AD genetics and associated physiological data into a common database to maximize statistical power to find therapeutic targets.

“Data-sharing and collaboration among cutting-edge research teams is key to advancing our understanding of complex genetic underpinnings of Alzheimer’s and related dementias,” said NIA director Richard Hodes, MD. “This new Center will play an important role in achieving our nation’s ultimate research goal, outlined under the National Plan to Address Alzheimer’s Disease to prevent and effectively treat Alzheimer’s disease by 2025.”

The Genomics Center will also bring in data from other non-NIA-funded studies, reprocess into a consistent format, and add to the common database housed at the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS), the national genetics data repository for Alzheimer’s disease developed and maintained by Wang’s team since 2012 and the Data Coordinating Center for the ADSP. The Genomic Center will amass genomic sequence data from subjects with Alzheimer’s disease and elderly cognitively normal subjects and use these data to identify genes that cause or protect against AD and other diseases.
“As the amount of data acquired increases, this will be a valuable resource for the study of other genetic disorders at Penn and other institutions,” Wang said.

The NIH Alzheimer’s Disease Sequencing Program (ADSP), a collaboration that also began in 2012 between NIA and the National Human Genome Research Institute (NHGRI), also part of NIH, has been analyzing data from 6,000 volunteers with Alzheimer’s disease and 5,000 older cognitively normal, unaffected individuals. In addition, the teams will study genomic data from 111 large families with multiple Alzheimer’s disease members, of Caucasian and Caribbean Hispanic descent to identify rare genetic variants. For the next phase of the project, the new Center will analyze new sequence data from an additional 3,000 AD cases.

George Washington University Researchers Receive $1.6 Million to Improve Cardiac Function During Heart Failure

Researchers at the George Washington University (GW) received $1.6 million from the National Heart, Lung, and Blood Institute to study a heart-brain connection that could help the nearly 23 million people suffering from heart failure worldwide. The four-year project will study ways to restore parasympathetic activity to the heart through oxytocin neuron activation, which could improve cardiac function during heart failure.

A distinctive hallmark of heart failure is autonomic imbalance, consisting of increased sympathetic activity and decreased parasympathetic activity. Parasympathetic activity is cardiac protective.

“Parasympathetic activity is what you have when you’re reading a book, or relaxing, and counteracts the sympathetic activity you have when you’re stuck on the metro or have an exam tomorrow,” said David Mendelowitz, Ph.D., vice chair and professor in the Department of Pharmacology and Physiology at the GW School of Medicine and Health Sciences. “Heart failure is a disease that effects both neuro and cardiac function.”

Unfortunately, few effective treatments exist to increase parasympathetic activity to the heart. Based upon exciting preliminary results, this study will examine the activation of neurons in the hypothalamus that release oxytocin, which has shown to increase parasympathetic activity in the heart. While oxytocin is often used to start or increase speed of labor, recent research has uncovered its role in feelings of generosity and bonding. It may also have beneficial effects on the heart.

The project is a collaboration between the GW School of Medicine and Health Sciences and the GW School of Engineering and Applied Science.

“While Dr. Mendelowitz’s research is focused on neuroscience and how the brain works, my work is focused on cardiac function. Heart failure is a disease that affects both, which is why it is imperative for Dr. Mendelowitz and I to use our complimentary expertise to solve this problem,” said Matthew Kay, PE, DSc, associate professor in the Department of Biomedical Engineering at the GW School of Engineering and Applied Science.

Kay and his research team will use high-speed optical assessments of heart function to identify heart-specific benefits of oxytocin nerve activation. Working together, Mendelowitz and Kay have the potential to unravel the complex interaction between the brain and the heart during heart failure.

Montefiore and Einstein Researchers Leverage Social Media to Uncover New Data on Migraine Sensory Experiences

A highly trafficked social media forum is yielding new findings on migraine symptoms, according to clinical researchers from the Montefiore Headache Center and Albert Einstein College of Medicine. A new report, “Special sensory experiences in migraine: a social media study,” reveals important disease epidemiology on migraine experiences like olfactory hallucinations, which may not be uncovered during traditional doctor/patient communications. Data from this study will be presented at the 58th Annual Meeting of the American Headache Society (AHS) being held June 9 – June 12 in San Diego.

Migraine ranks in the top 20 of the world’s most disabling medical illnesses, yet is underreported. While hallucinations around certain odors, noises and tastes have been known to occur during a migraine, these symptoms are not included in the International Headache Society classification. To garner more insights into these manifestations, researchers at Montefiore and Einstein tapped The Daily Migraine, a consumer-facing online forum to query 678 respondents through Facebook, Instagram and Twitter three times over three weeks, revealing new insights about experiences with certain tastes, sounds or smells in association with migraine attacks. Queries around olfactory hallucinations, most notably unpleasant smells like cigarette smoke and animal scents were what those with migraine most searched online. Queries also revealed ringing as the predominant migraine-associated sound. Unpleasant tastes, specifically a metallic taste, were also commonly searched.

“As researchers we have only scratched the surface of the depth of patient experience and disease information we can glean from social media channels,” said Matthew S. Robbins, M.D., FAHS, study author and director, Inpatient Services, Montefiore Headache Center, chief of Neurology, Jack D. Weiler Hospital and associate professor of Clinical Neurology, Einstein. “Using social media as a research tool, we learned more about migraine symptoms and what should be included during intake evaluations.”

The magnitude of migraine disability on everyday life causes missed work days, missed opportunities and events spent among family and friends, and can undermine the emotional, social and financial fabric of a family. A recent report published in Mayo Clinic Proceedings, from the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study, found that approximately 41% of people with migraine and 23% of spouses stated that they believed those impacted by migraine would be better parents if they did not have migraine, which consequently led to half of migraineurs missing at least one family activity in the past month.

“Given the onerous physical and emotional impact of migraine, an online forum is a unique resource to the professional headache community to help us improve how we diagnose, care for and treat headache and facial pain syndromes,” said Cynthia Armand, M.D., study author and chief resident, Department of Neurology, Montefiore and Einstein. “For individuals affected by these neurological diseases, an online site may provide more anonymity and a community, making it a safe place to be open and honest without fear of being judged or marginalized.”

From Nanotechnology, A Better Prognostic Tool For Brain Cancer

A new nano-fabricated platform for observing brain cancer cells provides a much more detailed look at how the cells migrate and a more accurate post-surgery prognosis for brain cancer (glioblastoma) patients.

By creating an environment similar to the one that glioblastoma cells naturally navigate, Yale and Hopkins researchers could accurately predict the clinical outcomes of the 14 brain cancer patients enrolled in a recent study. The results are published today[June9] in the journal Cell Reports. Glioblastoma is a highly invasive and rapidly progressing cancer that has resisted various types of treatment. Given a very short average survival expectancy, it is important to improve the diagnostic capabilities prior and at the time of the surgery.

Prof. Andre Levchenko, director of Yale‘s Systems Biology Institute and John C. Malone Professor of Biomedical Engineering, said the platform allows cells to be observed individually, and isolates a subset of particularly aggressive cells. This small group of cells plays a critical role in what makes glioblastoma such a deadly form of cancer.

“We can now analyze all these effects on the single-cell level, which is important because there are a multiple cell subpopulations in the tumor,” said Levchenko, a co-senior author of the study. “A tumor is a community of cells – not just one type of cell.”

Conversely, genetic analyses look at many different cells at once, and crucial details are lost. As a result, these tests offer scant information for predicting patient outcomes.

To create the appropriate environment, the researchers engineered a polymeric nanostructure that mimics certain aspects of brain tissue architecture. Unlike a flat and hard Petri dish, this environment provides cells with a fibrous structure.

In this environment – a sort of middle ground between 2-dimensional and 3-dimensional structures – the cells’ behavior mirrored that of cells in real brain tissue, particularly in the presence of platelet-derived growth factor (PDGF), a molecule naturally found in brain tumors.

“Surprisingly, we could predict how many months would pass before a specific tumor would recur by observing how the cells moved after being surgically removed,” Levchenko said.

Levchenko said introducing PDGF was key to seeing differences among patients. The cells reacted very strongly to PDGF in the cells of some patients, while there was little effect with other patients. The response to this cue was particularly strong in the subset of very aggressive cells. “That’s where the important differences between patients turned out to be,” Levchenko said.

For a comparison, the researchers also observed cells placed in a Petri dish. In that environment, the glioblastoma cells were much more passive and unresponsive to changes in chemical cues, including PDGF. This underscores the importance of placing patient cells into an appropriate environment for diagnostic and prognostic testing.

Besides developing a more precise prognosis, the researchers believe the technology could lead to new therapies and better match existing ones to specific patients, a goal of Yale Systems Biology Institute.

Botox’s Sweet Tooth Underlies Its Key Neuron-Targeting Mechanism UCI

The Botox toxin has a sweet tooth, and it’s this craving for sugars – glycans, to be exact – that underlies its extreme ability target neuron cells in the body … while giving researchers an approach to neutralize it.

A study co-led by Rongsheng Jin, professor of physiology & biophysics at the University of California, Irvine; Min Dong with Boston Children’s Hospital-Harvard Medical School; and Andreas Rummel with the Hannover Medical School in Germany, reveals an important general mechanism by which the pathogen is attracted to, adapts to and takes advantage of glycan modifications in surface receptors to invade motor neurons. Glycans are chains of sugars synthesized by cells for their development, growth, functioning or survival. Results appear June 13 in Nature Structural and Molecular Biology.

“Our findings reveal a new paradigm of the everlasting host-pathogen arms race, where a pathogen develops a smart strategy to achieve highly specific binding to a host receptor while also tolerating genetic changes on the receptor,” Jin said. “And to some extent, this mechanism by which the toxin attacks human is similar to the one that is utilized by some important broad-neutralizing human antibodies to fight viruses, such as dengue viruses and HIV.”

Botulinum neurotoxin A (BoNT/A), commonly known as the Botox toxin, is widely used in a weakened form for treating various medical conditions as well as for cosmetics. The clinical product Botox contains extremely low doses of the toxin and is safe to use. But at higher doses, it can be lethal, and it’s also classified as a potential bioterrorism agent.

Its potency and therapeutic effects rely on its extraordinary ability to target motor neurons and subsequently block release neurotransmitters that control the movement of muscle fiber, which can result in paralysis. This specific targeting is achieved by highly selective interactions between the toxin and its receptors – host proteins that bind to the toxin in a lock and key manner.

The intricate detail of how the Botox toxin recognizes its receptors also reveals novel ways to neutralizing these deadly toxins. “With this new structural information,” Rummel said, “we were able to pinpoint key amino acids in the toxin that are required for binding to sugars, and we found that even mutating a single amino acid is sufficient to abolish the toxicity by more than a million fold.”

Remarkably, the newly mapped glycan-binding site turns out to be also the site recognized by a potent human neutralizing antibody called CR2/CR1, which is currently in clinical trial for the treatment and prevention of BoNT/A poisoning. “This antibody fights the toxin exactly by preventing it from binding to sugars on the receptor. Our study thus provides a new strategy for anti-toxin inhibitor design,” Dong said.

Guorui Yao and Kwok-ho Lam at UCI, Sicai Zhang at Harvard, Stefan Mahrhold at the Hannover Medical School, Daniel Stern at Berlin’s Center for Biological Threats & Special Pathogens, Kay Perry at the Argonne National Laboratory in Illinois, and Karine Bagramyan and Markus Kalkum the Beckman Research Institute at the City of Hope in Duarte, Calif., contributed to the study, which was primarily supported by the National Institutes of Health.

Imaging Study Shows Promising Results for Patients with Schizophrenia

A team of scientists from across the globe have shown that the brains of patients with schizophrenia have the capacity to reorganize and fight the illness. This is the first time that imaging data has been used to show that our brains may have the ability to reverse the effects of schizophrenia.

Schizophrenia is an illness generally associated with a widespread reduction in brain tissue volume. However, a recent study found that a subtle increase in tissue also occurs in certain brain regions.

The study followed 98 patients with schizophrenia and compared them to 83 patients without schizophrenia. The team used Magnetic Resonance Imaging (MRI) and a sophisticated approach called covariance analysis to record the amount of brain tissue increase. Due to the subtlety and the distributed nature of increase, this had not been demonstrated in patients before now.

According to Lawson Health Research Institute’s Dr. Lena Palaniyappan, there is an overarching feeling that curing people with a severe mental illness, such as schizophrenia is not possible. “Even the state-of-art frontline treatments aim merely for a reduction rather than a reversal of the cognitive and functional deficits caused by the illness,” says Dr. Palaniyappan, who is the Medical Director at the Prevention & Early Intervention Program for Psychoses (PEPP) at London Health Sciences Centre (LHSC).

This comes from a long-standing notion that schizophrenia is a degenerative illness, with the seeds of damage sown very early during the course of brain development. “Our results highlight that despite the severity of tissue damage, the brain of a patient with schizophrenia is constantly attempting to reorganize itself, possibly to rescue itself or limit the damage,” says Dr. Palaniyappan.

The team’s next step is to clarify the evolution of this brain tissue reorganization process by repeatedly scanning individual patients with early schizophrenia and study the effect of this reorganization on their recovery.

“These findings are important not only because of their novelty and the rigour of the study, but because they point the way to the development of targeted treatments that potentially could better address some of the core pathology in schizophrenia,” explains Dr. Jeffrey Reiss, Site Chief, Psychiatry, LHSC. “Brain plasticity and the development of related therapies would contribute to a new optimism in an illness that was 100 years ago described as premature dementia for its seemingly progressive deterioration.”

“Dr. Palaniyappan and his colleagues have opened new avenues of research into our understanding of schizophrenia,” says Dr. Paul Links, Chair/Chief, Psychiatry, LHSC. “Their findings may lead us to be able to harness the brain’s own compensatory changes in the face of this illness and improve recovery. We are excited that Dr. Palaniyappan will be continuing this important clinical research here in London with his international colleagues.”