Finding challenges accepted view of MS: Unexpectedly, damaged nerve fibers survive

Multiple sclerosis, a brain disease that affects over 400,000 Americans, causes movement difficulties and many neurologic symptoms. MS has two key elements: The nerves that direct muscular movement lose their electrical insulation (the myelin sheath) and cannot transmit signals as effectively. And many of the long nerve fibers, called axons, degenerate.

Many scientists believe that axons are doomed once they lose the insulation, but a new study by graduate student Chelsey Smith and former undergraduate Elizabeth Cooksey in the Journal of Neuroscience shows axons can survive for long periods in rats even after losing myelin.

"This was the first study to demonstrate long-term axon survival after myelin deterioration," says senior author Ian Duncan, a professor in the School of Veterinary Medicine at the University of Wisconsin-Madison.

The mutant rats in the experiment have substantial myelin at first, but by eight weeks the essential myelin insulation is lost. “It was surprising,” says Duncan, an expert in MS pathology. “Nine months is a relatively long period in a rat’s lifetime, and there wasn’t a loss of axons, so the assumption that axons must automatically die without myelin seems incorrect.”

One in Three Children with Multiple Sclerosis has Cognitive Impairment

Data from the largest multicenter study accessing cognitive functioning in children with multiple sclerosis (MS) reveals that one-third of these patients have cognitive impairment, according to a research paper published in the Journal of Child Neurology. Led by Lauren B. Krupp, MD, Director of the Lourie Center for Pediatric Multiple Sclerosis at Stony Brook Long Island Children’s Hospital, the study indicates that patients experience a range of problems related to cognition.

In “Cognitive Impairment Occurs in Children and Adolescents with Multiple Sclerosis: Results from a United States Network,” Dr. Krupp and colleagues from Stony Brook and five other national Pediatric MS Centers of Excellence measured the cognitive functioning of 187 children and adolescents with MS, and 44 who experienced their first neurologic episode (clinically isolated syndrome) indicative of MS. They found that 35 percent of the patients with MS and 18 percent of those with clinically isolated syndrome met criteria for cognitive impairment. All patients were under age 18 with an average disease duration of about two years. 

“This study is important because it represents the largest study to date to apply a comprehensive neuropsychological battery of tests to evaluate the cognitive functioning of children with MS, and the results clearly show us that cognitive issues are widespread and can occur early on in the disease course of these patients,” said Dr. Krupp, also a Professor of Neurology at Stony Brook University School of Medicine. “These are critically important findings that emphasize the need for prompt recognition of our patients’ cognitive problems and for neurologists and other MS specialists to discover ways to intervene and help improve the cognitive abilities of these children while they are in school and beyond.”

Fighting fat with fat: stem cell discovery identifies potential obesity treatment

Ottawa scientists have discovered a trigger that turns muscle stem cells into brown fat, a form of good fat that could play a critical role in the fight against obesity. The findings from Dr. Michael Rudnicki’s lab, based at the Ottawa Hospital Research Institute, were published today in the prestigious journal Cell Metabolism.

"This discovery significantly advances our ability to harness this good fat in the battle against bad fat and all the associated health risks that come with being overweight and obese," says Dr. Rudnicki, a senior scientist and director for the Regenerative Medicine Program and Sprott Centre for Stem Cell Research at the Ottawa Hospital Research Institute. He is also a Canada Research Chair in Molecular Genetics and professor in the Faculty of Medicine at the University of Ottawa.

Globally, obesity is the fifth leading risk for death, with an estimated 2.8 million people dying every year from the effects of being overweight or obese, according to the World Health Organization. The Public Health Agency of Canada estimates that 25% of Canadian adults are obese.

Globally, obesity is the fifth leading risk for death, with an estimated 2.8 million people dying every year from the effects of being overweight or obese, according to the World Health Organization. The Public Health Agency of Canada estimates that 25% of Canadian adults are obese.

In 2007, Dr. Rudnicki led a team that was the first to prove the existence of adult skeletal muscle stem cells. In the paper published today, Dr. Rudnicki now shows (again for the first time) that these adult muscle stem cells not only have the ability to produce muscle fibres, but also to become brown fat. Brown fat is an energy-burning tissue that is important to the body’s ability to keep warm and regulate temperature. In addition, more brown fat is associated with less obesity.

Perhaps more importantly, the paper identifies how adult muscle stem cells become brown fat. The key is a small gene regulator called microRNA-133, or miR-133. When miR-133 is present, the stem cells turn into muscle fibre; when reduced, the stem cells become brown fat.

Dr. Rudnicki’s lab showed that adult mice injected with an agent to reduce miR-133, called an antisense oligonucleotide or ASO, produced more brown fat, were protected from obesity and had an improved ability to process glucose. In addition, the local injection into the hind leg muscle led to increased energy production throughout the body—an effect observed after four months.

Using an ASO to treat disease by reducing the levels of specific microRNAs is a method that is already in human clinical trials. However, a potential treatment using miR-133 to combat obesity is still years away.

"While we are very excited by this breakthrough, we acknowledge that it’s a first step," says Dr. Rudnicki, who is also scientific director of the Stem Cell Network. "There are still many questions to be answered, such as: Will it help adults who are already obese to lose weight? How should it be administered? How long do the effects last? Are there adverse effects we have not observed yet?"

The brain circuit that makes it hard for obese people to lose weight

Imagine you are driving a car, and the harder you press on the accelerator, the harder an invisible foot presses on the brake. That’s what happens when obese people diet – the less food they eat, the less energy they burn, and the less weight they lose.

While this phenomenon is known, scientists at Sydney’s Garvan Institute of Medical Research and the University of NSW have pinpointed the exact brain circuitry behind it and have published their findings in the prestigious international journal Cell Metabolism, now online.

Dr Shu Lin, Dr Yanchuan Shi and Professor Herbert Herzog and his team have been studying the complex processes behind energy balance using various mouse models. They have shown that the neurotransmitter Neuropeptide Y (NPY), known for stimulating appetite, also plays a major role in controlling whether the body burns or conserves energy.

The researchers found that NPY produced in a particular region of the brain – the arcuate nucleus (Arc) of the hypothalamus – inhibits the activation of ‘brown fat’, one of the primary tissues where the body generates heat.

“This study is the first to identify the neurotransmitters and neural pathways that carry signals generated by NPY in the brain to brown fat cells in the body. It is also the first to show a direct connection between Arc NPY, the sympathetic nervous system and the control of energy expenditure.” said Professor Herzog.

“We know that NPY also influences other aspects of the sympathetic nervous system – such as heart rate and gut function – but its control of heat generation through brown fat seems to be the most critical factor in the control of energy expenditure.”

“When you don’t eat, or dramatically curtail your calorie intake, levels of NPY rise sharply. High levels of NPY signal to the body that it is in ‘starvation mode’ and should try to replenish and conserve as much energy as possible. As a result, the body reduces processes that are not absolutely necessary for survival.”

“Evolution has provided us with these mechanisms to help us survive famine, and they are strictly controlled. When people had to survive by finding food or hunting game, they could not afford to run out of energy and die of exhaustion, so their bodies evolved to cope.”

“Until the twentieth century, there were no fast food chains and people did not have ready access to high fat, high sugar, foods. So in evolutionary terms, it was unlikely that people were going to get very fat and mechanisms were only put in place to prevent you losing weight.”

“Obesity is a modern epidemic, and the challenge will be to find ways of tricking the body into losing weight – and that will mean somehow circumventing or manipulating this NPY circuit, probably with drugs.”

Brain research provides clues to what makes people think and behave differently

Differences in the physical connections of the brain are at the root of what make people think and behave differently from one another. Researchers reporting in the February 6 issue of the Cell Press journal Neuron shed new light on the details of this phenomenon, mapping the exact brain regions where individual differences occur. Their findings reveal that individuals’ brain connectivity varies more in areas that relate to integrating information than in areas for initial perception of the world.

"Understanding the normal range of individual variability in the human brain will help us identify and potentially treat regions likely to form abnormal circuitry, as manifested in neuropsychiatric disorders," says senior author Dr. Hesheng Liu, of the Massachusetts General Hospital.

Dr. Liu and his colleagues used an imaging technique called resting-state functional magnetic resonance imaging to examine person-to-person variability of brain connectivity in 23 healthy individuals five times over the course of six months.

The researchers discovered that the brain regions devoted to control and attention displayed a greater difference in connectivity across individuals than the regions dedicated to our senses like touch and sight. When they looked at other published studies, the investigators found that brain regions previously shown to relate to individual differences in cognition and behavior overlap with the regions identified in this study to have high variability among individuals. The researchers were therefore able to pinpoint the areas of the brain where variable connectivity causes people to think and behave differently from one another.

Higher rates of variability across individuals were also displayed in regions of the brain that have undergone greater expansion during evolution. “Our findings have potential implications for understanding brain evolution and development,” says Dr. Liu. “This study provides a possible linkage between the diversity of human abilities and evolutionary expansion of specific brain regions,” he adds.

Green tea and red wine extracts interrupt Alzheimer’s disease pathway in cells

Natural chemicals found in green tea and red wine may disrupt a key step of the Alzheimer’s disease pathway, according to new research from the University of Leeds.

In early-stage laboratory experiments, the researchers identified the process which allows harmful clumps of protein to latch on to brain cells, causing them to die. They were able to interrupt this pathway using the purified extracts of EGCG from green tea and resveratrol from red wine.

The findings, published in the Journal of Biological Chemistry, offer potential new targets for developing drugs to treat Alzheimer’s disease, which affects some 800,000 people in the UK alone, and for which there is currently no cure.

"This is an important step in increasing our understanding of the cause and progression of Alzheimer’s disease," says lead researcher Professor Nigel Hooper of the University’s Faculty of Biological Sciences. "It’s a misconception that Alzheimer’s is a natural part of ageing; it’s a disease that we believe can ultimately be cured through finding new opportunities for drug targets like this."

Alzheimer’s disease is characterised by a distinct build-up of amyloid protein in the brain, which clumps together to form toxic, sticky balls of varying shapes. These amyloid balls latch on to the surface of nerve cells in the brain by attaching to proteins on the cell surface called prions, causing the nerve cells to malfunction and eventually die.

"We wanted to investigate whether the precise shape of the amyloid balls is essential for them to attach to the prion receptors, like the way a baseball fits snugly into its glove," says co-author Dr Jo Rushworth. "And if so, we wanted to see if we could prevent the amyloid balls binding to prion by altering their shape, as this would stop the cells from dying."

The team formed amyloid balls in a test tube and added them to human and animal brain cells. Professor Hooper said: “When we added the extracts from red wine and green tea, which recent research has shown to re-shape amyloid proteins, the amyloid balls no longer harmed the nerve cells. We saw that this was because their shape was distorted, so they could no longer bind to prion and disrupt cell function.

"We also showed, for the first time, that when amyloid balls stick to prion, it triggers the production of even more amyloid, in a deadly vicious cycle," he added.

Professor Hooper says that the team’s next steps are to understand exactly how the amyloid-prion interaction kills off neurons.

"I’m certain that this will increase our understanding of Alzheimer’s disease even further, with the potential to reveal yet more drug targets," he said.

Dr Simon Ridley, Head of Research at Alzheimer’s Research UK, the UK’s leading dementia research charity, which part-funded the study, said: “Understanding the causes of Alzheimer’s is vital if we are to find a way of stopping the disease in its tracks. While these early-stage results should not be a signal for people to stock up on green tea and red wine, they could provide an important new lead in the search for new and effective treatments. With half a million people affected by Alzheimer’s in the UK, we urgently need treatments that can halt the disease – that means it’s crucial to invest in research to take results like these from the lab bench to the clinic.”

'Bionic man' goes on show at British museum

A “bionic man” costing one million dollars went on display on Tuesday at Britain’s Science Museum, complete with artificial organs, synthetic blood and robot limbs.

Named Rex, which is short for “Robotic Exoskeleton”, the six foot six inch (two metre) humanoid with its uncannily life-like face was assembled by leading roboticists for a television programme.

Although cheaper than the “Six Million Dollar Man” made famous by the cult 1970s television series starring Lee Majors, the technology is far advanced from the fictional bionics on show back then.

The creation includes key advances in prosthetic technology, as well as an artificial pancreas, kidney, spleen and trachea and a functional blood circulatory system.

Welcoming Rex to the museum in London on Tuesday was Swiss social psychologist Bertolt Meyer, who was himself born without a left hand and has a sophisticated bionic replacement.

"I’ve looked around for new bionic technologies, out of personal interest, for a very long time and I think that until five or six years ago nothing much was happening," Meyer said.

"Then suddenly we are now at a point where we can build a body that is great and beautiful in its own special way."

The museum exhibit, which opens to the public on Thursday, will explore changing perceptions of human identity against the background of rapid progress in bionics—although Rex is not strictly bionic as he does not include living tissue.

Imaging Biomarker Predicts Response to Rapid Antidepressant

A telltale boost of activity at the back of the brain while processing emotional information predicted whether depressed patients would respond to an experimental rapid-acting antidepressant, a National Institutes of Health study has found.

“We have discovered a potential neuroimaging biomarker that may eventually help to personalize treatment selection by revealing brain-based differences between patients,” explained Maura Furey, Ph.D., of NIH’s National Institute of Mental Health (NIMH).

Furey, NIMH’s Carlos Zarate, M.D., and colleagues, reported on their functional magnetic resonance imaging (fMRI) study of a pre-treatment biomarker for the antidepressant response to scopolamine, Jan. 30, 2013, online in JAMA Psychiatry.

Scopolamine, better known as a treatment for motion sickness, has been under study since Furey and colleagues discovered its fast-acting antidepressant properties in 2006. Unlike ketamine, scopolamine works through the brain’s acetylcholine chemical messenger system. The NIMH team’s research has demonstrated that by blocking receptors for acetylcholine on neurons, scopolamine can lift depression in many patients within a few days; conventional antidepressants typically take weeks to work. But not all patients respond, spurring interest in a predictive biomarker.

The acetylcholine system plays a pivotal role in working memory, holding information in mind temporarily, but appears to act by influencing the processing of information rather than through memory. Imaging studies suggest that visual working memory performance can be enhanced by modulating acetylcholine-induced activity in the brain’s visual processing area, called the visual cortex, when processing information that is important to the task. Since working memory performance can predict response to conventional antidepressants and ketamine, Furey and colleagues turned to a working memory task and imaging visual cortex activity as potential tools to identify a biomarker for scopolamine response.

Depressed patients have a well-known tendency to process and remember negative emotional information. The researchers propose that this bias stems from dysregulated acetylcholine systems in some patients. They reasoned that such patients would show aberrant visual cortex activity in response to negative emotional features of a working memory task. They also expected to find that patients with more dysfunctional acetylcholine systems would respond better to scopolamine treatment.

The zebrafish revealed a central regulator for the development of the brain histamine system

Research has shown that mutations in the psen1 gene are common in the familial forms of Alzheimer’s disease, and the Presenilin-1 protein that the gene encodes is known to be involved in the cleavage of the amyloid precursor protein. In Alzheimer’s disease the amyloid precursor protein is not cleaved the normal way, and the protein accumulates in the brain damaging neuronal tracts and neurons. It is still unknown if the psen1 gene is involved in the etiology of Alzheimer’s disease via another mechanism.

Professor Pertti Panula’s research team at the University of Helsinki has elucidated the role of psen1 gene in the development of the neuronal histamine system and its modulation. Histamine is one of the neurotransmitters, which all are essential for cognitive functions, which in turn are impaired in Alzheimer’s disease. The histamine system is altered during the progression of Alzheimer’s disease.

In the study the zebrafish was used as a model organism. The rapidly developing zebrafish is suitable as a model organism, as its transparency allows researchers to study the development and function of vital organs. To study the function of psen1 gene, zebrafish that did not produce functional Presenilin-1 protein were generated. Despite the fact that the fish lacked functional Presenilin-1 they were viable and developed until adulthood.

The lack of Presenilin-1 protein induced a change in the behavior of the larval zebrafish, they did not as normal fish react to fast changes in the light intensity. “Based on previous research we know that this change in behavior is associated with lack of histamine in the brain”, Panula explains.

In adulthood the motor behavior of the mutant zebrafish differed from the normal fish: the fish swam by the edges of the arena that was available and avoided the inner part. Previous studies from the group have shown that this behavioral alteration also is due to changes in the histamine system.

The researchers found that larval fish lacking Presenilin-1 protein had significantly fewer histamine neurons; in adulthood the histamine neuron number was significantly increased in these fish when compared with normal fish.

"These results reveal that the psen1 gene is a central regulator of the development of the histamine neurons and that the mutation can cause a persistent lifelong change in the neuronal histamine system. This is a very interesting finding", Panula states.

One interesting remaining question is from where the new histamine neurons arise in the brains of adult zebrafish. Are they newly differentiated stem cells or do other cells become histamine neurons? The answer is not known, but based on these results it is advisable to elucidate the role of Presenilin-1 protein in differentiation of stem cells also in the brains of mammals. “Mammals have stem cells in the hypothalamus, in the same area where the histamine neurons are located in all studied vertebrates”, Panula comments.

Panula empathizes that the published study does not tell about an Alzheimer’s disease mechanism in humans. The new knowledge on the function of psen1 gene and the development of the brain histamine system provided by the study is one step forward to understanding the etiology of the disease.

"We perform basic research on molecular level, from where it is a long way to treatment of human diseases. This type of research provides the findings on which the treatments are finally based", Panula says.

Journal of Neuroscience published the study that was conducted at University of Helsinki Neuroscience center, and Institute of Biomedicine.

(Image: Charles Badland, Florida State University)