Posts tagged brain

ScienceDaily (June 29, 2012) — Cognitive skills such as learning and memory diminish with age in everyone, and the drop-off is steepest in Alzheimer’s disease. Texas scientists seeking a way to prevent this decline reported exciting results this week with a drug that has Polynesian roots.

Easter Island statues. (Credit: © Celsius / Fotolia)

The researchers, appointed in the School of Medicine at The University of Texas Health Science Center San Antonio, added rapamycin to the diet of healthy mice throughout the rodents’ life span. Rapamycin, a bacterial product first isolated from soil on Easter Island, enhanced learning and memory in young mice and improved these faculties in old mice, the study showed.

"We made the young ones learn, and remember what they learned, better than what is normal," said Veronica Galvan, Ph.D., assistant professor of physiology at the Barshop Institute for Longevity and Aging Studies, part of the UT Health Science Center. "Among the older mice, the ones fed with a diet including rapamycin actually showed an improvement, negating the normal decline that you see in these functions with age."

The drug also lowered anxiety and depressive-like behavior in the mice, Dr. Galvan said. Anxiety and depression are factors that impair human cognitive performance. Lead author Jonathan Halloran conducted scientifically reliable tests to accurately measure these cognitive components in the rodents.

Venturing into the open

Mice are burrowers that prefer tunnels with walls. To observe behavior, Halloran used an elevated maze of tunnels that led to a catwalk. “All of a sudden the mice are in open space,” Halloran said. “It’s pretty far from the floor for their size, sort of like if a person is hiking and suddenly the trail gets steep. It’s pretty far down and not so comfortable.”

Mice with less anxiety were more curious to explore the catwalk. “We observed that the mice fed with a diet containing rapamycin spent significantly more time out in the open arms of the catwalk than the animals fed with a regular diet,” Halloran said.

The second test measured depressive-like behavior in the rodents. Mice do not like to be held by their tails, which is the way they are moved from cage to cage. Inevitably they struggle to find a way out. “So we can measure how much and how often they struggle as a measure of the motivation they have to get out of an uncomfortable situation,” Dr. Galvan said.

Rapamycin acts like an antidepressant

Some mice barely struggle to get free, but if an antidepressant is administered they struggle a lot more. This behavior is very sensitive to the action of antidepressants and is a reliable measure of whether a drug is acting like an antidepressant, Dr. Galvan said.

"We found rapamycin acts like an antidepressant — it increases the time the mice are trying to get out of the situation," she said. "They don’t give up; they struggle more."

The reductions of anxiety and depressive-like behavior in rapamycin-treated mice held true for all ages tested, from 4 months of age (college age in human years) to 12 months old (the equivalent of middle age) to 25 months old (advanced age).

Feel-good chemicals elevated

The researchers measured levels of three “happy, feel-good” neurotransmitters: serotonin, dopamine and norepinephrine. All were significantly augmented in the midbrains of mice treated with rapamycin. “This is super-interesting, something we are going to pursue in the lab,” Dr. Galvan said.

Dr. Galvan and her team published research in 2010 showing that rapamycin rescues learning and memory in mice with Alzheimer’s-like deficits. The elevation of the three neurotransmitters, which are chemical messengers in the brain, may explain how rapamycin accomplished this, Dr. Galvan said.

Rapamycin is an antifungal agent administered to transplant patients to prevent organ rejection. The drug is named for Rapa Nui, the Polynesian title for Easter Island. This island, 2,000 miles from any population centers, is the famed site of nearly 900 mysterious monolithic statues.

Source: Science Daily

ScienceDaily (June 28, 2012) — Johns Hopkins researchers, working with an international consortium, say they have generated stem cells from skin cells from a person with a severe, early-onset form of Huntington’s disease (HD), and turned them into neurons that degenerate just like those affected by the fatal inherited disorder.

By creating “HD in a dish,” the researchers say they have taken a major step forward in efforts to better understand what disables and kills the cells in people with HD, and to test the effects of potential drug therapies on cells that are otherwise locked deep in the brain.

Although the autosomal dominant gene mutation responsible for HD was identified in 1993, there is no cure. No treatments are available even to slow its progression.

The research, published in the journal Cell Stem Cell, is the work of a Huntington’s Disease iPSC Consortium, including scientists from the Johns Hopkins University School of Medicine in Baltimore, Cedars-Sinai Medical Center in Los Angeles and the University of California, Irvine, as well as six other groups. The consortium studied several other HD cell lines and control cell lines in order to make sure results were consistent and reproducible in different labs.

The general midlife onset and progressive brain damage of HD are especially cruel, slowly causing jerky, twitch-like movements, lack of muscle control, psychiatric disorders and dementia, and — eventually — death. In some cases (as in the patient who donated the material for the cells made at Johns Hopkins), the disease can strike earlier, even in childhood.

"Having these cells will allow us to screen for therapeutics in a way we haven’t been able to before in Huntington’s disease," saysChristopher A. Ross, M.D., Ph.D., a professor of psychiatry and behavioral sciences, neurology, pharmacology and neuroscience at the Johns Hopkins University School of Medicine and one of the study’s lead researchers. "For the first time, we will be able to study how drugs work on human HD neurons and hopefully take those findings directly to the clinic."

Ross and his team, as well as other collaborators at Johns Hopkins and Emory University, are already testing small molecules for the ability to block HD iPSC degeneration.These small molecules have the potential to be developed into novel drugs for HD.

The ability to generate from stem cells the same neurons found in Huntington’s disease may also have implications for similar research in other neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

To conduct their experiment, Ross took a skin biopsy from a patient with very early onset HD.When seen by Ross at the HD Center at Hopkins, the patient was just seven years old. She had a very severe form of the disease, which rarely appears in childhood, and of the mutation that causes it. Using cells from a patient with a more rapidly progressing form of the disease gave Ross’ team the best tools with which to replicate HD in a way that is applicable to patients with all forms of HD.

Her skin cells were grown in culture and then reprogrammed by the lab of Hongjun Song, Ph.D., a professor at Johns Hopkins’ Institute for Cell Engineering, into induced pluripotent stem cells. A second cell line was generated in an identical fashion in Dr. Ross’s lab from someone without HD. Simultaneously, other HD and control iPS cell lines were generated as part of the NINDS funded HD iPS cell consortium.

Scientists at Johns Hopkins and other consortium labs converted those cells into generic neurons and then into medium spiny neurons, a process that took three months. What they found was that the medium spiny neurons deriving from HD cells behaved just as they expected medium spiny neurons from an HD patient would. They showed rapid degeneration when cultured in the lab using basic culture medium without extensive supporting nutrients. By contrast, control cell lines did not show neuronal degeneration.

"These HD cells acted just as we were hoping," says Ross, director of the Baltimore Huntington’s Disease Center. "A lot of people said, ‘You’ll never be able to get a model in a dish of a human neurodegenerative disease like this.’ Now, we have them where we can really study and manipulate them, and try to cure them of this horrible disease. The fact that we are able to do this at all still amazes us."

Specifically, the damage caused by HD is due to a mutation in the huntingtin gene (HTT), which leads to the production of an abnormal and toxic version of the huntingtin protein. Although all of the cells in a person with HD contain the mutation, HD mainly targets the medium spiny neurons in the striatum, part of the brain’s basal ganglia that coordinates movement, thought and emotion. The ability to work directly with human medium spiny neurons is the best way, researchers believe, to determine why these specific cells are susceptible to cell stress and degeneration and, in turn, to help find a way to halt progression of HD.

Much HD research is conducted in mice. And while mouse models have been helpful in understanding some aspects of the disease, researchers say nothing compares with being able to study actual human neurons affected by HD.

For years, scientists have been excited about the prospect of making breakthroughs in curing disease through the use of stem cells, which have the remarkable potential to develop into many different cell types. In the form of embryonic stem cells, they do so naturally during gestation and early life. In recent years, researchers have been able to produce induced pluripotent stem cells (iPSCs), which are adult cells (like the skin cells used in Ross’s experiments) that have been genetically reprogrammed back to the most primitive state. In this state, under the right circumstances, they can then develop into most or all of the 200 cell types in the human body.

Source: Science Daily

ScienceDaily (June 28, 2012) — We’ve all heard that eating fish is good for our brains and memory. But what is it about DHA, an omega-3 fatty acid found in fish, that makes our memory sharper?

Researchers with the Faculty of Medicine & Dentistry discovered a possible explanation and just published their findings in the peer-reviewed journal Applied Physiology, Nutrition, and Metabolism.

Principal investigator Yves Sauve and his team discovered lab models fed a high-DHA diet had 30 per cent higher levels of DHA in the memory section of the brain, known as the hippocampus, when compared to animal models on a regular, healthy diet.

"We wanted to find out how fish intake improves memory," says Sauve, a medical researcher at the University of Alberta who works in the department of physiology, the department of ophthalmology and the Centre for Neuroscience.

"What we discovered is that memory cells in the hippocampus could communicate better with each other and better relay messages when DHA levels in that region of the brain were higher. This could explain why memory improves on a high-DHA diet."

Sauve noted it is a key finding that when a diet is supplemented with DHA, that additional stores of the omega-3 fatty acid are deposited in the brain. His team confirmed this finding, a discovery other labs have noted as well.

Supplementing your diet with DHA, such as increasing fish intake or taking supplements, could prevent declining DHA levels in the brain as we age, says Sauve.

This research was funded by Alberta Innovates — Health Solutions.

Earlier this year, Sauve and other colleagues discovered DHA prevents the accumulation of a toxic molecule at the back of the eye that causes age-related vision loss. He is continuing his research in this area.

Source: Science Daily

June 28, 2012

Researchers have come up with a device that may enable people who are completely unable to speak or move at all to nevertheless manage unscripted back-and-forth conversation. The key to such silent and still communication is the first real-time, brain-scanning speller, according to the report published online on June 28 in Current Biology.

Researchers have come up with a device that may enable people who are completely unable to speak or move at all to nevertheless manage unscripted back-and-forth conversation. The key to such silent and still communication is the first real-time, brain-scanning speller, according to the report published online on June 28 in Current Biology.

The new technology builds on groundbreaking earlier uses of fMRI brain scans to assess consciousness in people described as being in an unconscious, vegetative state and to enable them to answer yes and no questions. fMRI (or functional magnetic resonance imaging) is typically used for clinical and research purposes to track brain activity by measuring blood flow.

"The work of Adrian Owen and colleagues led me to wonder whether it might even become possible to use fMRI, mental tasks, and appropriate experimental designs to freely encode thoughts, letter-by-letter, and therewith enable back-and-forth communication in the absence of motor behavior,” said Bettina Sorger of Maastricht University in The Netherlands.

[Video]
This video shows mental task-related brain activation patterns. Video (c) Current Biology

The new evidence shows that the answer to that thought question is yes. Sorger’s team came up with a letter-encoding technique that requires almost no pre-training. Participants in their study voluntarily selected letters on a screen, which guided the letter encoding; for each specific character, participants were asked to perform a particular mental task for a set period of time. That produced 27 distinct brain patterns corresponding to each letter of the alphabet and the equivalent of a space bar, which could be automatically decoded in real-time using newly developed data analysis methods.

In each communication experiment, participants held a mini-conversation consisting of two open questions and answers. Everyone the researchers tested was able to successfully produce answers within a single one-hour session.

The results substantially extend earlier uses of fMRI, which allowed individuals to answer the equivalent of multiple-choice questions having four or fewer possible answers, by enabling free-letter spelling. That could make all the difference for people who are completely paralyzed and unable to benefit from other means of alternative communication, Sorger says.

Ultimately, she says their goal is to transfer the fMRI technology they’ve developed to a more portable and affordable method for measuring blood flow, such as functional near-infrared spectroscopy (fNIRS).

Source: medicalxpress.com

June 28, 2012

In a genome-wide association (GWA) study, researchers from Boston University Schools of Medicine (BUSM) and Public Health (BUSPH) have identified several genes which influence degeneration of the hippocampus, the part of the brain most associated with Alzheimer disease (AD). The study, which currently appears online as a Rapid Communication in the Annals of Neurology, demonstrates the efficacy of endophenotypes for broadening the understanding of the genetic basis of and pathways leading to AD.

AD is a progressive neurodegenerative disorder for which there are no prevention methods. Available drugs only marginally affect disease severity and progression, making AD effectively untreatable.

GWA studies using very large samples have increased the number of robust associations to 10 genes, including APOE. However, these genes account for no more than 35 percent of the inherited risk of AD and most of the genetic underpinning of the disorder remains unexplained. According to the researchers, magnetic resonance imaging (MRI) of the brain provides in vivo quantitative measures of neurodegenerative and cerebrovascular brain injury that may represent AD-related changes long before clinical symptoms appear. These measures are more powerful than comparisons of individuals with AD with cognitively healthy persons because they avoid misclassification of normal persons who will develop disease in the future.

BUSM researchers conducted a two-stage GWA study for quantitative measures of hippocampal volume (HV), total cerebral volume (TCV) and white matter hyperintensities (WMH). Brain MRI measures of HV, TCV and WMH were obtained from 981 Caucasian and 419 African-American AD cases and their cognitively normal siblings in the MIRAGE (Multi Institutional Research in Alzheimer’s Genetic Epidemiology) Study. In addition, similar MRI measures were obtained from 168 AD cases, 336 individuals with mild cognitive impairment and 188 controls (all Caucasian) in the AD Neuroimaging Initiative (ADNI) Study. The MIRAGE Caucasian families and ADNI subjects were included in the first stage and the MIRAGE African American families were added in stage two. Results from the two Caucasians data sets were combined by meta-analysis.

In stage two, one genetic marker (i.e. single nucleotide polymorphism or SNP) from each of the gene regions that were most significantly associated with AD in the Caucasian data sets was evaluated in the African-American data set.

Novel genome-wide significant associations were observed for HV with SNPs in the APOE, F5/SELP, LHFP, and GCFC2 gene regions. All of these associations were supported by evidence in each data set.

"Our two-stage GWAS identified highly significant associations between a measure of degeneration in the brain region most strongly correlated with AD and several genes in both Caucasian and African American samples containing AD, cognitively impaired and cognitively healthy subjects. One of these associations was with the ε4 variant of APOE which is the most well-established genetic risk factor for AD.

Other associations were demonstrated with markers in F5/SELP, LHFP, and GCFC2, genes not previously implicated in this disease” explained senior author Lindsay Farrer, PhD, chief of biomedical genetics at BUSM. He also noted, “previous studies showed that blood level of P-selectin (the protein encoded by SELP) has been correlated with rate of cognitive decline in AD patients.”

Farrer believes it is very likely that the number and specificity of these associations will increase in future studies using larger samples and focused on additional precise structural and functional MRI measures. “These findings will inform experiments designed to increase our understanding of disease-causing mechanism and may lead to new therapeutics targets,” added Farrer.

Provided by Boston University Medical Center

Source: medicalxpress.com

June 28, 2012

In a process akin to belling an infinitesimal cat, scientists have managed to tag a protein that regulates the neurotransmitter serotonin with tiny fluorescent beads, allowing them to track the movements of single molecules for the first time.

This is a microphotograph of neurons with their serotonin transporter protein labeled with red quantum dots. Credit: Jerry Chang, Vanderbilt University

The capability, which took nearly a decade to achieve, makes it possible to study the dynamics of serotonin regulation at a new level of detail, which is important because of the key role that serotonin plays in the regulation of mood, appetite and sleep.

The achievement was reported by an interdisciplinary team of Vanderbilt scientists in the June 27 issue of the Journal of Neuroscience.

The regulatory protein that the scientists successfully tagged is known as the serotonin transporter. This is a protein that extends through the membrane that forms the nerve’s outer surface and acts like a nano-sized vacuum cleaner that sucks serotonin molecules into the cell body and away from serotonin target receptors on other cells. In this fashion it helps regulate the concentration of serotonin in the area around the cell. Serotonin transporters are an important research subject because they are the target for the most common drugs used to treat depression, including Prozac, Paxil and Lexapro.

"If you are interested in mental health, then serotonin transporters are an ideal subject," said Sandra Rosenthal, the Jack and Pamela Egan Chair of Chemistry, who directed the study with Randy Blakely, the Allan D. Bass Professor of Pharmacology and Psychiatry.

Problems with serotonin transporter regulation have also been implicated in autism. Two years ago, Blakely and geneticist James Sutcliffe, associate professor of molecular physiology and biophysics, reported the discovery of multiple changes in the serotonin transporter protein that cause the transporter to become “overactive” in subjects with autism. Recently, Blakely and Assistant Professor of Psychiatry Jeremy Veenstra-VanderWeele reported that mice expressing one of these high-functioning transporters exhibit multiple behavioral changes that resemble changes seen in kids with autism.

The brain’s other key neurotransmitters have their own transporter proteins, so scientists can use the capability to track the motion of individual transporter molecules to determine how they are regulated as well.

Attempts to understand how these transporters work have been limited by the difficulty of studying their dynamic behavior. “In the past, we have been limited to snapshots that show the location of transporter molecules at a specific time,” said chemistry graduate student Jerry Chang, who developed the tagging technique. “Now we can follow their motion on the surface of cells in real time and see how their movements relate to serotonin uptake activity.”

The fluorescent tags that the researchers used are nanoscale beads called quantum dots made from a mixture of cadmium and selenium. These beads are only slightly bigger than the proteins they are tagging: You would have to string 10,000 together to span the width of a human hair.

Quantum dots emit colored light when illuminated and have the useful property that small changes in their size cause them to glow in different colors. Team member Ian D. Tomlinson, assistant research professor of chemistry, developed a special molecular string that attaches to the quantum dot at one end and, on the other end, attaches to a drug derivative that binds exclusively with the serotonin transporter. When a mixture that contains these quantum dots is incubated with cultured nerve cells, the drug attaches to the transporter. As the protein moves around, it drags the quantum dot behind it like a child holding a balloon on a string. When the area is illuminated, the quantum dots show up in a microscope as colored points of light.

"Until now, neurobiologists have had to rely on extremely low resolution approaches where it takes the signals coming from thousands to millions of molecules to be detected," said Blakely, "We really had no idea exactly what we were going to see."

Putting their new procedure to use, the researchers looked at extensions of the nerve cell that are involved in secreting serotonin on the presumption that transporters would be localized there as well. From previous research, the investigators suspected that the transporters would be concentrated in cholesterol-rich parts of these extensions, termed rafts, although the level of resolution with standard approaches was inadequate to provide any clues as to what they were doing there.

The quantum dot studies demonstrated that there were two distinct populations of transporters in these areas: Those that can travel freely around the membrane and those that act as if they are unable to move. They found that the immobile transporters were located in the rafts. When they stimulated the cell to increase transporter activity, they were surprised at what happened. “We found that the transporters in the rafts began to move much faster whereas the motion of the other population didn’t change at all,” Rosenthal reported. Since the mobilized transporters do not leave the rafts, they appear to whizz around inside a confined compartment, as if released from chains that normally keep them subdued. These observations suggest it is likely that the two populations are controlled by different regulatory pathways.

"Now that we can watch transporter regulation actually happening, we should be able to figure out the identity of the anchoring proteins and the signals these proteins respond to that permit transporters to switch back and forth between low and high activity levels," said Blakely.

"Currently, antidepressant drugs must fully shut down the brain’s serotonin transporters to achieve a clinical benefit," the pharmacologist said. Such a manipulation can produce a number of unpleasant side-effects, such as nausea, weight gain, sexual problems, fatigue and drowsiness.

"By understanding the basic mechanisms that naturally turn serotonin transporter activity up and down, maybe we can develop medications that produce milder side-effects and have even greater efficacy," he said. "Our sights are also focused on transferring what we have learned with normal serotonin transporters to an understanding of the hyperactive transporters we have found in kids with autism.”

Provided by Vanderbilt University

Source: medicalxpress.com

June 28, 2012

(Medical Xpress) — New research has shed light on the high risk of fractures, falls, and osteoporosis among epilepsy patients using antiepileptic drugs with most patients unaware of the risks associated with taking the drugs.

The study led by the University of Melbourne and published in the prestigious Neurology journal, found that people taking antiepileptic drugs are up to four times more likely to suffer spine, collarbone and ankle fractures and are more likely to have been diagnosed with osteoporosis.

The study also revealed that these patients are more than four times as likely as non-users of antiepileptic drugs to have been diagnosed with osteoporosis.

In addition, treatment affected balance with results showing almost double the falls rate in female patients taking the medication compared with non-users.

Chief Investigator, Prof John Wark from the University of Melbourne’s Department of Medicine at the Royal Melbourne Hospital said this research revealed new information critical to understanding the higher risk for fractures and falls in epilepsy patients taking antiepileptic medication.

“We believe patients need to be offered better information to help them to avoid these risks and prevent injury,” he said.

More than 70 percent of epilepsy patients who participated in the study were unaware of the increased risk of fractures, decreased bone mineral density and falls associated with taking antiepileptic medications.

“No published studies have explored epilepsy patients’ awareness of the effects of AEDs on bone health, fracture risk and falls.  This study indicates that awareness of these issues is poor, despite our study population attending specialist epilepsy clinics at a centre with a major interest in this area,” said Prof Wark.

“Most patients indicated they would like to be better informed about these issues, suggesting that more effective education strategies are warranted and would be well-received.”

“Epilepsy patients should be assessed regularly for their history of falls and fractures for appropriate management strategies to be offered.”

The study compared 150 drug users with 506 non-users.  All drug users were epilepsy outpatients at the Royal Melbourne Hospital, over 15 years old and had been taking AEDs for a minimum of three months.

Provided by University of Melbourne

Source: medicalxpress.com

ScienceDaily (June 27, 2012) — Modern anesthesia is extremely safe. But as risks to heart, lungs and other organs have waned, another problem has emerged in the elderly: post-operative cognitive dysfunction. Mentally, some patients “just aren’t the same” for months or longer after surgery. Other factors play a role, but a small number of patients deteriorate mentally due to anesthesia per se. Those with Alzheimer’s disease suffer exacerbations, and those without the diagnosis may have it unmasked by anesthesia, suggesting some relationship.

Alzheimer’s disease has two types of brain lesions. Beta-amyloid deposits accumulate outside neurons but don’t cause cognitive problems. Neurofibrillary tangles inside neurons, composed of hyper-phosphorylated ‘tau’, a protein normally attached to microtubules, do correlate with dementia. These same tau tangles are found in post-anesthesia dementia.

Microtubules (MTs) polymerize from ‘tubulin’ proteins to grow, shape and regulate neurons. Synaptic components are transported by motor proteins which move like railroad trains along MT tracks. In branching dendrites, motors change MTs repeatedly to reach their destination. Tau is a traffic signal, telling motors where to get on and off, the route encoded in MT binding sites for tau.

That MTs process information stems from Charles Sherrington in the 1950s, with recent controversial suggestions of MT computing, and even quantum computing mediating consciousness and memory. But whether MTs play a primary, or mere supportive role, their stability and function are essential to cognition and consciousness.

Excessive phosphorylation had been thought the culprit in detaching tau and causing tangles. But destabilized MTs now appear to be the primary problem in both Alzheimer’s and post-anesthesia dementia, releasing tau which then becomes hyperphosphorylated. Anesthetics are known to bind to tubulin, in some cases for days after exposure, and in high doses to cause MT disassembly.

Now, in a study in PLoS ONE, a team from Canada, Portugal and the USA report molecular modeling showing 32 anesthetic binding sites per tubulin, with at least 1 percent (10 million) of the billion tubulins per brain neuron binding an anesthetic molecule at clinical concentration (1 ‘MAC’). Two particular anesthetic binding regions may destabilize MTs, one inactivating tubulin C-termini tails (which otherwise knit together neighboring tubulins). The other weakens side-to-side tubulin couplings, the critical link in MT lattices, but only at high anesthetic concentrations, or perhaps with other MT destabilizing factors (low temperature, low zinc, high calcium, acidosis).

Travis Craddock PhD, lead author on the study said: “The good news is that therapies aimed at microtubule stabilization may help in both Alzheimer’s and post-anesthetic dementias. Clinical trials are underway, or planned, for microtubule stabilizers Epothilone D, NAPVSIPQ, and the zinc ionophore PBT2, as well as brain ultrasound, shown in vitro to excite MT resonances and promote polymerization. However it’s done, ‘tightening the tubules’ may best treat dementia.”

Source: Science Daily