Posts tagged neuroscience

The St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project has identified mutations responsible for more than half of a subtype of childhood brain tumor that takes a high toll on patients. Researchers also found evidence the tumors are susceptible to drugs already in development.

The study focused on a family of brain tumors known as low-grade gliomas (LGGs). These slow-growing cancers are found in about 700 children annually in the U.S., making them the most common childhood tumors of the brain and spinal cord. For patients whose tumors cannot be surgically removed, the long-term outlook remains bleak due to complications from the disease and its ongoing treatment. Nationwide, surgery alone cures only about one-third of patients.

Using whole genome sequencing, researchers identified genetic alterations in two genes that occurred almost exclusively in a subtype of LGG termed diffuse LGG. This subtype cannot be cured surgically because the tumor cells invade the healthy brain. Together, the mutations accounted for 53 percent of the diffuse LGG in this study. Researchers also demonstrated that one of the mutations, which had not previously been linked to brain tumors, caused tumors when introduced into the glial brain cells of mice.

The findings appear in the April 14 advance online edition of the scientific journal Nature Genetics.

“This subtype of low-grade glioma can be a nasty chronic disease, yet prior to this study we knew almost nothing about its genetic alterations,” said David Ellison, M.D., Ph.D., chair of the St. Jude Department of Pathology and the study’s corresponding author. The first author is Jinghui Zhang, Ph.D., an associate member of the St. Jude Department of Computational Biology.

The Pediatric Cancer Genome Project is using next-generation whole genome sequencing to determine the complete normal and cancer genomes of children and adolescents with some of the least understood and most difficult to treat cancers. Scientists believe that studying differences in the 3 billion chemical bases that make up the human genome will provide the scientific foundation for the next generation of cancer care.

“We were surprised to find that many of these tumors could be traced to a single genetic alteration,” said co-author Richard K. Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis. “This is a major pathway through which low-grade gliomas develop and it provides new clues to explore as we search for better treatments.”

The study involved whole genome sequencing of 39 paired tumor and normal tissue samples from 38 children and adolescents with different subtypes of LGG and related tumors called low-grade glioneuronal tumors (LGGNTs). Although many cancers develop following multiple genetic abnormalities, 62 percent of the 39 tumors in this study stemmed from a single genetic alteration.

Previous studies have linked LGGs to abnormal activation of the MAPK/ERK pathway. The pathway is involved in regulating cell division and other processes that are often disrupted in cancer. Until now, however, the genetic alterations involved in driving this pathway were unknown for some types of LGG and LGGNT.

This study linked activation in the pathway to duplication of a key segment of the FGFR1 gene, which investigators discovered in brain tumors for the first time. The segment is called a tyrosine kinase domain. It functions like an on-off switch for several cell signaling pathways, including the MAPK/ERK pathway. Investigators also demonstrated that experimental drugs designed to block activity along two altered pathways worked in cells with theFGFR1 tyrosine kinase domain duplication. “The finding suggests a potential opportunity for using targeted therapies in patients whose tumors cannot be surgically removed,” Ellison said.

Researchers also showed that the FGFR1 abnormality triggered an aggressive brain tumor in glial cells from mice that lacked the tumor suppressor gene Trp53.

Whole-genome sequencing found previously undiscovered rearrangements in the MYB and MYBL1 genes in diffuse LGGs. These newly identified abnormalities were also implicated in switching on the MAPK/ERK pathway.

Researchers checked an additional 100 LGGs and LGGNTs for the same FGFR1, MYB and MYBL1 mutations. Overall, MYB was altered in 25 percent of the diffuse LGGs, and 24 percent had alterations in FGFR1. Researchers also turned up numerous other mutations that occurred in just a few tumors. The affected genes included BRAF, RAF1, H3F3A, ATRX, EP300, WHSC1 and CHD2.

“The Pediatric Cancer Genome Project has provided a remarkable opportunity to look at the genomic landscape of this disease and really put the alterations responsible on the map. We can now account for the genetic errors responsible for more than 90 percent of low-grade gliomas,” Ellison said. “The discovery that FGFR1 and MYB play a central role in childhood diffuse LGG also serves to distinguish the pediatric and adult forms of the disease.”

(Source: stjude.org)

Research has shown that healthy behaviors are associated with a lower risk of Alzheimer’s disease and dementia, but less is known about the potential link between positive lifestyle choices and milder memory complaints, especially those that occur earlier in life and could be the first indicators of later problems.

To examine the impact of these lifestyle choices on memory throughout adult life, UCLA researchers and the Gallup organization collaborated on a nationwide poll of more than 18,500 individuals between the ages of 18 and 99. Respondents were surveyed about both their memory and their health behaviors, including whether they smoked, how much they exercised and how healthy their diet was.

As the researchers expected, healthy eating, not smoking and exercising regularly were related to better self-perceived memory abilities for most adult groups. Reports of memory problems also increased with age. However, there were a few surprises.

Older adults (age 60–99) were more likely to report engaging in healthy behaviors than middle-aged (40–59) and younger adults (18–39), a finding that runs counter to the stereotype that aging is a time of dependence and decline. In addition, a higher-than-expected percentage of younger adults complained about their memory.

"These findings reinforce the importance of educating young and middle-aged individuals to take greater responsibility for their health — including memory — by practicing positive lifestyle behaviors earlier in life," said the study’s first author, Dr. Gary Small, director of the UCLA Longevity Center and a professor of psychiatry and biobehavioral sciences at the Semel Institute for Neuroscience and Human Behavior at UCLA who holds the Parlow–Solomon Chair on Aging.

Published in the June issue of International Psychogeriatrics, the study may also provide a baseline for the future study of memory complaints in a wide range of adult age groups.

For the survey, Gallup pollsters conducted land-line and cell phone interviews with 18,552 adults in the U.S. The inclusion of cell phone–only households and Spanish-language interviews helped capture a representative 90 percent of the U.S. population, the researchers said.

"We found that the more healthy lifestyle behaviors were practiced, the less likely one was to complain about memory issues," said senior author Fernando Torres-Gil, a professor at UCLA’s Luskin School of Public Affairs and associate director of the UCLA Longevity Center.

In particular, the study found that respondents across all age groups who engaged in just one healthy behavior were 21 percent less likely to report memory problems than those who didn’t engage in any healthy behaviors. Those with two positive behaviors were 45 percent less likely to report problems, those with three were 75 percent less likely, and those with more than three were 111 percent less likely.

Interestingly, the poll found that healthy behaviors were more common among older adults than the other two age groups. Seventy percent of older adults engaged in at least one healthy behavior, compared with 61 percent of middle-aged individuals and 58 percent of younger respondents.

In addition, only 12 percent of older adults smoked, compared with 25 percent of young adults and 24 percent of middle-aged adults, and a higher percentage of older adults reported eating healthy the day before being interviewed (80 percent) and eating five or more daily servings of fruits and vegetables during the previous week (64 percent).

According to the researchers, older adults may participate in more healthy behaviors because they feel the consequences of unhealthy living and take the advice of their doctors to adopt healthier lifestyles. Or there simply could be fewer older adults with bad habits, since they may not live as long.

While 26 percent of older adults and 22 percent of middle-aged respondents reported memory issues, it was surprising to find that 14 percent of the younger group complained about their memory too, the researchers said.

"Memory issues were to be expected in the middle-aged and older groups, but not in younger people," Small said. "A better understanding and recognition of mild memory symptoms earlier in life may have the potential to help all ages."

Small said that, generally, memory issues in younger people may be different from those that plague older generations. Stress may play more of a role. He also noted that the ubiquity of technology — including the Internet, texting and wireless devices that can result in constant multi-tasking, especially with younger people — may impact attention span, making it harder to focus and remember.

Small noted that further study and polling may help tease out such memory-complaint differences. Either way, he said, the survey reinforces the importance, for all ages, of adopting a healthy lifestyle to help limit and forestall age-related cognitive decline and neurodegeneration.

The Gallup poll used in the study took place between December 2011 and January 2012 and was part of the Gallup–Healthways Well-Being Index, which includes health- and lifestyle-related polling questions. The five questions asked were: (1) Do you smoke? (2) Did you eat healthy all day yesterday? (3) In the last seven days, on how many days did you have five or more servings of vegetables and fruits? (4) In the last seven days, on how many days did you exercise for 30 minutes or more? (5) Do you have any problems with your memory? 

(Source: newsroom.ucla.edu)

Research at Lund University in Sweden gives hope that one of the most serious types of brain tumour, glioblastoma multiforme, could be fought by the patients’ own immune system. The tumours are difficult to remove with surgery because the tumour cells grow into the surrounding healthy brain tissue. A patient with the disease therefore does not usually survive much longer than a year after the discovery of the tumour.

The team has tested different ways of stimulating the immune system, suppressed by the tumour, with a ‘vaccine’. The vaccine is based on tumour cells that have been genetically modified to start producing substances that activate the immune system. The modified tumour cells (irradiated so that they cannot divide and spread the disease) have been combined with other substances that form part of the body’s immune system.

The treatment has produced good results in animal experiments: 75 per cent of the rats that received the treatment were completely cured of their brain tumours.

“Human biology is more complicated, so we perhaps cannot expect such good results in patients. However, bearing in mind the poor prognosis patients receive today, all progress is important”, said doctoral student Sara Fritzell, part of the research group led by consultant Peter Siesjö.

She has previously tested combining the activation of the immune system with chemotherapy. When the chemotherapy was applied directly to the tumour site, the positive effects reinforced each other, and a huge 83 per cent of the mice survived.

“Our idea is in the future to give patients chemotherapy locally in conjunction with the operation to remove as much of the tumour as possible”, said Sara Fritzell.

Peter Siesjö is currently applying for permission to carry out a clinical study on stimulation of the immune system – with or without local chemotherapy – as a treatment for patients with glioblastoma multiforme.

(Source: lunduniversity.lu.se)

GLYX-13, a molecular cousin to ketamine, induces similar antidepressant results without the street drug side effects, reported a study funded by the National Institute of Mental Health (NIMH) that was published last month in Neuropsychopharmacology.

Caption: Neurons in a subsection of the adult rat hippocampus are stained with a monoclonal antibody (yellow) that enhances learning and memory. A portion of this antibody is where GLYX-13 came from. (Source: Dr. Joseph Moskal, Ph.D., Northwestern University)

Background

Major depression affects about 10 percent of the adult population and is the second leading cause of disability in U.S. adults, according to the World Health Organization. Despite the availability of several different classes of antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs), 30 to 40 percent of adults are unresponsive to these medications. Moreover, SSRIs typically take weeks to work, which increases the risk for suicide.

Enter NMDA (N-methyl-D-aspartate) receptor modulators. In the 1970s, researchers linked the receptors to learning and memory. Biotech and pharmaceutical companies in the 1980s attempted to apply chemical blockers to these receptors as a means to prevent stroke. But blocking these receptors led to the opposite effect——the rise of cardiovascular disease. Research in the field dampened until a glutamate receptor antagonist already approved for anesthesia, and known on the streets as “Special K”, ketamine, made headlines in the early 2000s. Human clinical studies demonstrated that ketamine can ward off major and bipolar depressive symptoms within 2 hours of administration and last for several days. Ketamine is fraught with serious side effects including excessive sleepiness, hallucinations, and substance abuse behavior.

“Ketamine lit the field back up,“ said Joseph Moskal, Ph.D., a molecular neurobiologist at Northwestern University and senior study author. “Our drug, GLYX-13, is very different. It does not block the receptor ion channel, which may account for why it doesn’t have the same side effects.”

Moskal’s journey with GLYX-13 came about from his earlier days as a Senior Staff Fellow in NIMH’s Intramural Research Program. While at NIMH, he created specific molecules, monoclonal antibodies, to use as new probes to understand pathways of learning and memory. Some of the antibodies he created were for NMDA receptors. When he moved to Northwestern University, Moskal converted the antibodies to small protein molecules. Comprised of only four amino acids, GLYX-13 is one of these molecules.

Previous electrophysiological and conditioning studies had suggested that GLYX-13, unlike ketamine, enhanced memory and learning in rats, particularly in the brain’s memory hub or hippocampus. GLYX-13 also produced analgesic effects. Using several rat behavioral and molecular experiments, Moskal’s research team tested four compounds: GLYX-13, an inactive, “scrambled” version of GLYX-13 that had its amino acids rearranged, ketamine, and the SSRI fluoxetine.

Results of the Study

GLYX-13 and ketamine produced rapid acting (1 hour) and long-lasting (24 hour) antidepressant-like effects in the rats. Fluoxetine, an SSRI that typically takes from 2–4 weeks to show efficacy in humans, did not produce a rapid antidepressant effect in this study. As expected, the scrambled GLYX-13 showed no antidepressant-like effects at all. The researchers observed none of the aforementioned side effects of ketamine in the GLYX-13–treated rats.

Protein studies indicated an increase in the hippocampus of the NMDA receptor NR2B and a receptor for the chemical messenger glutamate called AMPA. Electrophysiology studies in this brain region showed that GLYX-13 and ketamine promoted long-lasting signal transmission in neurons, known as long-term potentiation/synaptic plasticity. This phenomenon is essential in learning and memory. The researchers propose how GLYX-13 works: GLYX-13 triggers NR2B receptor activation that leads to intracellular calcium influx and the expression of AMPA, which then is responsible for increased communication between neurons.

These results are consistent with data from a recent Phase 2 clinical trial, in which a single administration of GLYX-13 produced statistically significant reductions in depression scores in patients who had failed treatment with current antidepressants. The reductions were evident within 24 hours and persisted for an average of 7 days. After a single dose of GLYX-13, the drug’s antidepressant efficacy nearly doubled that seen with most conventional antidepressants after 4–6 weeks of dosing. GLYX-13 was well tolerated and it did not produce any of the schizophrenia-like effects associated with other NMDA receptor modulating agents.

Significance

NMDA receptors need a molecule each of the amino acid chemical messengers glutamate and glycine to become activated. Moskal speculates that GLYX-13 either directly binds to the glycine site on the NMDA receptor or indirectly modulates how glycine works with the receptor. Resulting activation of more NMDA and AMPA receptors leads to an increase in memory, learning—and antidepressant effects. By contrast, ketamine only blocks the NMDA receptor, but also increases the activity of the AMPA receptor. Knowledge of these mechanisms could lead to the development of more effective antidepressants.

What’s next

GLYX-13 is now being tested in a Phase 2 repeated dose antidepressant trial, where Moskal and his colleagues at Naurex, Inc., a biotechnology company he founded, hope to find in humans the optimal dosing for the drug. They also want to see if this molecule, and others like it, regulate other NMDA receptor subtypes—there are over 20 of them—and whether it will work on other disorders, such as schizophrenia, attention-deficit hyperactivity disorder, and autism.

“One could call NMDA modulators such as GLYX-13 ‘comeback kids,’” said Moskal. “A toolkit that I developed in 1983 is now setting the stage in 2013 for the development of possible new therapeutics that may provide individuals suffering from depression with a valuable new treatment option.”

Extremely low doses of marijuana’s psychoactive component protect brain before and after injury, says TAU researcher

Though marijuana is a well-known recreational drug, extensive scientific research has been conducted on the therapeutic properties of marijuana in the last decade. Medical cannabis is often used by sufferers of chronic ailments, including cancer and post-traumatic stress disorder, to combat pain, insomnia, lack of appetite, and other symptoms.

Now Prof. Yosef Sarne of Tel Aviv University’s Adelson Center for the Biology of Addictive Diseases at the Sackler Faculty of Medicine says that the drug has neuroprotective qualities as well. He has found that extremely low doses of THC — the psychoactive component of marijuana — protects the brain from long-term cognitive damage in the wake of injury from hypoxia (lack of oxygen), seizures, or toxic drugs. Brain damage can have consequences ranging from mild cognitive deficits to severe neurological damage.

Previous studies focused on injecting high doses of THC within a very short time frame — approximately 30 minutes — before or after injury. Prof. Sarne’s current research, published in the journals Behavioural Brain Research and Experimental Brain Research, demonstrates that even extremely low doses of THC — around 1,000 to 10,000 times less than that in a conventional marijuana cigarette — administered over a wide window of 1 to 7 days before or 1 to 3 days after injury can jumpstart biochemical processes which protect brain cells and preserve cognitive function over time.

This treatment, especially in light of the long time frame for administration and the low dosage, could be applicable to many cases of brain injury and be safer over time, Prof. Sarne says.

Conditioning the brain

While performing experiments on the biology of cannabis, Prof. Sarne and his fellow researchers discovered that low doses of the drug had a big impact on cell signalling, preventing cell death and promoting growth factors. This finding led to a series of experiments designed to test the neuroprotective ability of THC in response to various brain injuries.

In the lab, the researchers injected mice with a single low dose of THC either before or after exposing them to brain trauma. A control group of mice sustained brain injury but did not receive the THC treatment. When the mice were examined 3 to 7 weeks after initial injury, recipients of the THC treatment performed better in behavioral tests measuring learning and memory. Additionally, biochemical studies showed heightened amounts of neuroprotective chemicals in the treatment group compared to the control group.

The use of THC can prevent long-term cognitive damage that results from brain injury, the researchers conclude. One explanation for this effect is pre- and post-conditioning, whereby the drug causes minute damage to the brain to build resistance and trigger protective measures in the face of much more severe injury, explains Prof. Sarne. The low dosage of THC is crucial to initiating this process without causing too much initial damage.

Preventative and long-term use

According to Prof. Sarne, there are several practical benefits to this treatment plan. Due to the long therapeutic time window, this treatment can be used not only to treat injury after the fact, but also to prevent injury that might occur in the future. For example, cardiopulmonary heart-lung machines used in open heart surgery carry the risk of interrupting the blood supply to the brain, and the drug can be delivered beforehand as a preventive measure. In addition, the low dosage makes it safe for regular use in patients at constant risk of brain injury, such as epileptics or people at a high risk of heart attack.

Prof. Sarne is now working in collaboration with Prof. Edith Hochhauser of the Rabin Medical Center to test the ability of low doses of THC to prevent damage to the heart. Preliminary results indicate that they will find the same protective phenomenon in relation to cardiac ischemia, in which the heart muscle receives insufficient blood flow.

(Source: aftau.org)

University of Leicester researchers have contributed to a landmark study which has revealed a new way to treat strokes caused by bleeding inside the brain.

The study found that intensive blood pressure lowering in patients with intracerebral haemorrhage, the most serious type of stroke, reduced the risk of major disability and improved chances of recovery by as much as 20 per cent.

The study, which involved more than 2800 patients from 140 hospitals around the world, was announced today at the European Stroke Conference in London, and published in The New England Journal of Medicine.

Professor Thompson Robinson, Deputy Head of the University of Leicester’s Department of Cardiovascular Sciences, was the UK co-ordinator for the study and co-authored the paper.

The study was led by the George Institute for Global Health, in Sydney, Australia.

Professor Thompson Robinson said: “Stroke is the third most common cause of death in the UK and the most common adult cause of neurological disability. Approximately 1 million people are living with the consequences of stroke in the United Kingdom, a third with life-changing severe disability. Every year an estimated 152,000 people in the UK have a stroke and intracerebral haemorrhage - spontaneous bleeding within the brain most often due to hypertension - accounts for at least 10 per cent of all cases.

“Intracerebral haemorrhage kills about half of those affected within one month and leaves most survivors disabled, and to date there is no specific treatment for this type of stroke.

“The results of the study show that intensively reducing high blood pressure within 6 hours of onset of a bleeding-related stroke is safe, and results in a significant shift from being dead and dependent to being alive and independent after stroke. Because it involves treatment with already available blood pressure-lowering treatments, the results should be easy to implement in all hospitals and be of benefit to patients. It is important to reinforce that stroke is a medical emergency, and individuals who suspect that they may have had a stroke should dial 999 and seek urgent medical attention.

“Leicester has a long-standing interest in acute stroke and blood pressure research, and hosts the NIHR Trent Stroke Local Research Network. There are many opportunities for Leicester patients presenting with stroke to participate in research to improve outcomes for future patients with stroke.”

Professor Bruce Neal of The George Institute and The University of Sydney said the study challenges previous thought about blood pressure lowering in intracerebral haemorrhage.

He said: “The study findings will mean significant changes to guidelines for stroke management worldwide. They show that early intensive blood pressure lowering, using widely available therapies, can significantly improve the outcome of this illness.

“We hope to see hospital emergency departments around the world implement the new treatment as soon as possible. By lowering blood pressure, we can slow bleeding in the brain, reduce damage and enhance recovery.

“The study findings are tremendously exciting because they provide a safe and efficient treatment to improve the likelihood of a recovery without serious disability - a major concern for those who have experienced stroke.

“The only treatment option to date has been risky brain surgery, so this research is a very welcome advance.”

The study found patients who suffered an acute intracerebral haemorrhage and received the blood pressure lowering treatment were better off from both a physical and psychological perspective.

(Source: www2.le.ac.uk)

Researchers at Lund University in Sweden have identified the molecular mechanism behind the transformation of one of the components in Alzheimer’s disease. They identified the crucial step leading to formations that kill brain cells.

Alzheimer’s disease is associated with memory loss and personality changes. It is still not known what causes the onset of the disease, but once started it cannot be stopped. The accumulation of plaques in the brain is widely considered a hallmark of the disease. The key discovery identified the chemical reaction that causes the plaques to grow exponentially.

Amyloid beta, a protein fragment that occurs naturally in the fluid around the brain, is one of the building blocks of plaques. However, the processes leading from soluble amyloid beta to the form found in the plaques, known as amyloid fibril, have not been known. In the very early part of the process, two protein fragments can create a nucleus that then grows into a fibril.

In solution this is a slow process, but the rate can be enhanced on surfaces. The current study shows that fibrils present a catalytic surface where new nuclei form and this reaction increases the speed of the process. As soon as the first fibrils are formed, amyloid-beta fragments attach at its surface and form new fibrils that subsequently detach.

This process is thus self-perpetuating, and autocatalytic, and the more fibrils are present, the quicker the new ones are created, says Sara Snogerup Linse, Professor of Chemistry at Lund University and one of the researchers behind the study.

The findings also show that the chemical reaction on the fibril surface creates cell-killing formations. It is hoped that the research could lead to a new type of medication targeting early stages of the disease in the future.

The results have emerged from several years of laboratory work by Professor Snogerup Linse and her colleague in Lund, Erik Hellstrand, including development of extensive methods to obtain amyloid beta in highly pure form and to study its transformation in a highly reproducible manner. Additional methodology based on isotope labelling and spin filters was developed to monitor the surface catalysis and pin-point the origin of the forms that kill brain cells. The collaboration with the theoretical group and cell biologists at Cambridge University has been absolutely crucial for all the findings.

(Source: alphagalileo.org)