Orchestral manoeuvres: multiple sclerosis faces the music

The conductor walks to the stand and takes his place in front of the orchestra. He raises his baton and, with a dramatic flourish, one hundred individuals come to life. From nowhere, the stillness becomes a beautiful harmony as each member takes their part in a complex symphony.

Consider the workings and structure of the human brain – our most complicated organ – in terms of this orchestra. When it works, it is capable of something more remarkable than the greatest musical compositions in human history, but when it is affected by a condition such as multiple sclerosis (MS), “the brain’s tightly orchestrated biological functions become discordant – the conductor begins to fail at their job and several instruments go out of tune,” said Professor Robin Franklin, Head of Translational Science at the Wellcome Trust-Medical Research Council (MRC) Cambridge Stem Cell Institute and Director of the MS Society Cambridge Centre for Myelin Repair.

His research team and those led by other Stem Cell Institute researchers Drs Thóra Káradóttir, Mark Kotter and Stefano Pluchino are each looking at a different aspect of this errant orchestra. They hope that their collective knowledge will one day help ‘re-tune’ the brains of MS patients to self-repair.

In its simplest terms, MS is a disease in which the immune system turns on itself, destroying the oligodendrocytes that make a protective sheath called myelin, which encases nerve fibres. This halts the transmission of neural messages, and eventually leads to nerve fibre damage, resulting in a progressive loss of movement, speech and vision for the 100,000 people in the UK who have MS.

However, the complexities of treating the disease go beyond simply stopping the destruction of myelin, said Franklin: “The myelin damage causes a build-up of debris, which needs removing, and the environment surrounding the cells needs to be conducive to regenerating the sheath. When we think about repairing the damage, we need to be considering several different biological phenomena at the same time.”

Although there are drugs available for modifying the early stages of MS – including alemtuzumab (Lemtrada), developed in Cambridge – there are no treatments that regenerate the damaged tissue. Moreover, although the disease evolves over decades, with periods of remission followed by relapses, there is no treatment once patients have reached the progressive stage (estimated to be about 50% of current patients).

Oligodendrocytes – the master manufacturers of myelin – are formed by a type of stem cell in the brain called oligodendrocyte progenitor cells (OPCs), and are responsible for re-wrapping, or remyelinating, the bare axons with myelin in response to injuries or diseases. But this regenerative ability decreases with age and MS. “As the disease progresses, the need for intervention that galvanises the natural healing process becomes ever more important,” explained Franklin. “Working with colleagues at the Harvard Stem Cell Institute, we’ve shown that the effects of age on remyelination are reversible, which gives us some confidence that we can use the brain’s own OPCs for myelin regeneration.”

However, to understand how to stimulate the brain’s own repair mechanisms first requires an understanding of how the brain detects injury and initiates repair.

Thóra Káradóttir believes that one way the brain ‘senses’ problems are afoot is through the drop in how fast neural messages are passed across the brain. “The difference in speed between an intact neuron and a damaged one can be like comparing the speed of a cheetah to a tortoise,” she said. “I’m eavesdropping on the information superhighway by attaching electrodes to neurons and OPCs.”

Her findings show that damaged fibres release a molecule called glutamate. “It’s their ‘cry for help’ to OPCs. If it doesn’t happen, or if the OPCs don’t ‘hear’, then repair is reduced.” She is working with Numedicus, a company that specialises in developing secondary uses for existing drugs, to test drugs that she hopes will be able to amplify this signal and increase the repair process.

Meanwhile, Robin Franklin’s team has shown that it’s possible to kick-start OPCs, driving the formation of oligodendrocytes and sheath formation, using a drug that targets retinoid X receptor-gamma, a molecule found within OPCs. The results are positive and clinical trials will shortly commence in collaboration with Dr Alasdair Coles from the Department of Clinical Neurosciences and the MRC Centre for Regenerative Medicine at the University of Edinburgh.

What’s interesting about the rejuvenation of remyelination is that the treatment primarily affected inflammation in demyelinating lesions, and specifically the recruitment of cells called macrophages. These are the body’s ‘big eaters’ – their role is to search out and gobble up rubbish. “We have identified myelin debris as a potent inhibitor of stem cells. Learning how it is being sensed by stem cells enabled us to overcome this inhibition by using drugs such as ibudilast.  A clinical trial to test these effects is currently undergoing preparation,” explained Mark Kotter.

Franklin and Kotter’s work is representative of an interesting turn in MS research within the field. Increasingly, investigators are looking at how the environment around the damage can be improved to help natural remyelination. “It’s a curious paradox,” said Franklin. “MS is caused by the immune system but components of the immune system are also key to its recovery.”

Stefano Pluchino’s team, for instance, has shown that injecting brain stem cells into mice with MS works in a surprising way. Instead of making new oligodendrocytes (or other brain cells), the cells seem to work by re-setting the damaging immune response, creating better conditions for the brain’s own stem cells to replace or restore what has been damaged. He is now developing more-efficient stem cells and new drugs, including nanomedicines, to foster the healing of the damaged brain.

Given the complex landscape of abnormal activities happening in the MS brain, will combination therapies be the way forward? “Certainly,” said Franklin. “Over the next ten years we will see an increased understanding of the fundamental biology in MS, we will identify more targets which may yield effective drugs and we’ll have more-refined strategies for running clinical trials. What makes Cambridge rare is the spectrum of skills here – from understanding the fundamental biology of myelin repair through to clinical trials.”

Scientists track the rise and fall of brain volume throughout life

We can witness our bodies mature, then gradually grow wrinkled and weaker with age, but it is only recently that scientists have been able to track a similar progression in the nerve bundles of our brains. That tissue increases in volume until around age 40, then slowly shrinks. By the end of our lives the tissue is about the volume of a 7-year-old.

So finds a team of Stanford scientists who used a new magnetic resonance imaging technique to show, for the first time, how human brain tissue changes throughout life. Knowing what’s normal at different ages, doctors can now image a patient’s brain, compare it to this standard curve and be able to tell if a person is out of the normal range, much like the way a growth chart can help identify kids who have fallen below their growth curve. The researchers have already used the technique to identify previously overlooked changes in the brain of people with multiple sclerosis.

"This allows us to look at people who have come into the clinic, compare them to the norm and potentially diagnose or monitor abnormalities due to different diseases or changes due to medications," said Jason Yeatman, a graduate student in psychology and first author on a paper published today in Nature Communications. Aviv Mezer, a research associate, was senior author on the paper. Both collaborated with Brian Wandell, a professor of psychology, and his team.

For decades scientists have been able to image the brain using magnetic resonance imaging (MRI) and detect tumors, brain activity or abnormalities in people with some diseases, but those measurements were all subjective. A scientist measuring some aspect of the brain in one lab couldn’t directly compare findings with someone in another lab. And because no two scans could be compared, there was no way to look at a patient’s image and know whether it fell outside the normal range.

Limitation overcome

"A big problem in MRI is variation between instruments," Mezer said. Last year Mezer and Wandell led an interdisciplinary team to develop a technique that can be used to compare MRI scans quantitatively between labs, described in Nature Medicine. “Now with that method we found a way to measure the underlying tissue and not the instrumental bias. So that means that we can measure 100 subjects here and Jason can measure another 100 in Seattle (where he is now a postdoctoral fellow) and we can put them all in a database for the community.”

The technique the team had developed measures the amount of white matter tissue in the brain. That amount of white matter comes primarily from an insulating covering called myelin that allows nerves to fire most efficiently and is a hallmark of brain maturation, though the white matter can also be composed of other types of cells in the brain.

White matter plays a critical role in brain development and decline, and several diseases including schizophrenia and autism are associated with white matter abnormalities. Despite its importance in normal development and disease, no metric existed for determining whether any person’s white matter fell within a normal range, particularly if the people were imaged on different machines.

Mezer and Yeatman decided to use the newly developed quantitative technique to develop a normal curve for white matter levels throughout life. They imaged 24 regions within the brains of 102 people ages 7 to 85, and from that established a set of curves showing the increase and then eventual decrease in white matter in each of the 24 regions throughout life.

What they found is that the normal curve for brain composition is rainbow-shaped. It starts and ends with roughly the same amount of white matter and peaks between ages 30 and 50. But each of the 24 regions changes a different amount. Some parts of the brain, like those that control movement, are long, flat arcs, staying relatively stable throughout life.

Others, like the areas involved in thinking and learning, are steep arches, maturing dramatically and then falling off quickly. (The group did point out that their samples started at age 7 and a lot of brain development had already occurred.)

Continued collaboration

"Regions of the brain supporting high-level cognitive functions develop longer and have more degradation," Yeatman said. "Understanding how that relates to cognition will be really important and interesting." Yeatman is now a postdoctoral scholar at the University of Washington, and Mezer is now an assistant professor at the Hebrew University of Jerusalem. They plan to continue collaborating with each other and with other members of the Wandell lab, looking at how brain composition correlates with learning and how it could be used to diagnose diseases, learning disabilities or mental health issues.

The group has already shown that they can identify people with multiple sclerosis (MS) as falling outside the normal curve. People with MS develop what are known as lesions – regions in the brain or spinal cord where myelin is missing. In this paper, the team showed that they could identify people with MS as being off the normal curve throughout regions of the brain, including places where there are no visible lesions. This could provide an alternate method of monitoring and diagnosing MS, they say.

Wandell has had a particular interest in studying the changes that happen in the brain as a child learns to read. Until now, if a family brought a child into the clinic with learning disabilities, Wandell and other scientists had no way to diagnose whether the child’s brain was developing normally, or to determine the relationship between learning delays and white matter abnormalities.

"Now that we know what the normal distribution is, when a single person comes in you can ask how their child compares to the normal distribution. That’s where this is headed," said Wandell, who is also the Isaac and Madeline Stein Family professor and a Stanford Bio-X affiliate. Wandell runs the Center for Cognitive and Neurobiological Imaging (CNI), where Mezer and the team developed the MRI technique to quantify white matter, and where the scans for this study were conducted.

The ability to share data among scientists is an issue Wandell has championed at the CNI and has been promoting in his work helping the Stanford Neurosciences Institute plan the computing strategy for their new facility. “Sharing of data and computational methods is critical for scientific progress,” Wandell said. In line with that goal, the new standard curve for white matter is something scientists around the world can use and contribute data to.

(Image caption: Example axial sections of a three-dimensional MPF map (A) obtained from a 63-year old woman with SPMS disease course and results of brain tissue segmentation (B-D). Segmentation masks corresponding to white matter (WM) (B), gray matter (GM) (C), and lesi)

MRI Shows Gray Matter Myelin Loss Strongly Related to MS Disability

People with multiple sclerosis (MS) lose myelin in the gray matter of their brains and the loss is closely correlated with the severity of the disease, according to a new magnetic resonance imaging (MRI) study. Researchers said the findings could have important applications in clinical trials and treatment monitoring. The study appears online in the journal Radiology.

Loss of myelin, the fatty protective sheath around nerve fibers, is a characteristic of MS, an inflammatory disease of the central nervous system that can lead to a variety of serious neurological symptoms and disability. MS is typically considered a disease of the brain’s signal-conducting white matter, where myelin is most abundant, but myelin is also present in smaller amounts in gray matter, the brain’s information processing center that is made up primarily of nerve cell bodies. Though the myelin content in gray matter is small, it is still extremely important to proper function, as it enables protection of thin nerve fibers connecting neighboring areas of the brain cortex, according to Vasily L. Yarnykh, Ph.D., associate professor in the Department of Radiology at University of Washington in Seattle.

“The fact that MS patients lose myelin not only in white but also in gray matter has been proven by earlier post-mortem pathological studies,” he said. “However, the clinical significance of the myelin loss, or demyelination, in gray matter has not been established because of the absence of appropriate imaging methods.”

To learn more about associations between MS and demyelination in both white and gray matter, Dr. Yarnykh and colleagues used a refined MRI technique that provides information on the content of biological macromolecules – molecules present in tissues and composed of a large number of atoms, such as proteins, lipids and carbohydrates. The new method, known as macromolecular proton fraction (MPF) mapping, has been hampered in the past because of the length of time required for data collection, but improvements now allow much faster generation of whole-brain maps that reflect the macromolecular content in tissues.

“The method utilizes a standard MRI scanner and doesn’t require any special hardware—only some software modifications,” Dr. Yarnykh said. “MPF mapping allows quantitative assessment of microscopic demyelination in brain tissues that look normal on clinical images, and is the only existing method able to evaluate the myelin content in gray matter.”

The researchers looked at 30 MS patients, including 18 with relapsing-remitting MS (RRMS), the most common type of MS initially diagnosed, and 12 with the more advanced type of disease known as secondary progressive MS (SPMS). Fourteen healthy control participants were also included in the study. Each participant underwent MRI on a 3-Tesla imager, and the researchers reconstructed 3-D whole-brain MPF maps to look at normal-appearing white matter, gray matter and MS lesions. The researchers further compared the results of their imaging technique with clinical tests characterizing neurological dysfunction in MS patients.

The results showed that MPF was significantly lower in both white and gray matter in RRMS patients compared with healthy controls, and was also significantly reduced in both normal-appearing brain tissues and lesions of SPMS patients compared to RRMS patients with the largest relative decrease in gray matter. MPF in brain tissues of MS patients significantly correlated with clinical disability and the strongest associations were found for gray matter.

“The major finding of the study is that the loss of myelin in gray matter caused by MS in its relative amount is comparable to or even larger than that in white matter,” said Dr. Yarnykh. “Furthermore, gray matter demyelination is much more advanced in patients with secondary-progressive MS, and it is very strongly related to patients’ disability. As such, we believe that information about gray matter myelin damage in MS is of primary clinical relevance.”

The improved technique has potentially important applications for MS treatments targeted to protect and restore myelin.

“First, this method may provide an objective measure of the disease progression and treatment success in clinical trials,” Dr. Yarnykh said. “And second, assessment of both gray and white matter damage with this method may become an individual patient management tool in the future.”

Dr. Yarnykh and colleagues are currently conducting additional research on the new method with the support of the National Multiple Sclerosis Society and the National Institutes of Health.

“This study was done on the participants at a single point in time,” he said. “Now we want to compare MS patients with control participants to see how myelin content will evolve over time. We further plan to extend our method to the spinal cord imaging and test whether the combined assessment of demyelination in the brain and spinal cord could better explain disability progression as compared to brain demyelination alone.”

(Image caption: Aggressor cells, which have the potential to cause autoimmunity, are targeted by treatment, causing conversion of these cells to protector cells. Gene expression changes gradually at each stage of treatment, as illustrated by the color changes in this series of heat maps. Credit: University of Bristol/Dr. Bronwen Burton)

Scientists discover how to ‘switch off’ autoimmune diseases

Scientists have made an important breakthrough in the fight against debilitating autoimmune diseases such as multiple sclerosis by revealing how to stop cells attacking healthy body tissue.

Rather than the body’s immune system destroying its own tissue by mistake, researchers at the University of Bristol have discovered how cells convert from being aggressive to actually protecting against disease.

The study, funded by the Wellcome Trust, is published in Nature Communications.

It’s hoped this latest insight will lead to the widespread use of antigen-specific immunotherapy as a treatment for many autoimmune disorders, including multiple sclerosis (MS), type 1 diabetes, Graves’ disease and systemic lupus erythematosus (SLE).

MS alone affects around 100,000 people in the UK and 2.5 million people worldwide.

Scientists were able to selectively target the cells that cause autoimmune disease by dampening down their aggression against the body’s own tissues while converting them into cells capable of protecting against disease.

This type of conversion has been previously applied to allergies, known as ‘allergic desensitisation’, but its application to autoimmune diseases has only been appreciated recently.

The Bristol group has now revealed how the administration of fragments of the proteins that are normally the target for attack leads to correction of the autoimmune response.

Most importantly, their work reveals that effective treatment is achieved by gradually increasing the dose of antigenic fragment injected.

In order to figure out how this type of immunotherapy works, the scientists delved inside the immune cells themselves to see which genes and proteins were turned on or off by the treatment.

They found changes in gene expression that help explain how effective treatment leads to conversion of aggressor into protector cells. The outcome is to reinstate self-tolerance whereby an individual’s immune system ignores its own tissues while remaining fully armed to protect against infection.

By specifically targeting the cells at fault, this immunotherapeutic approach avoids the need for the immune suppressive drugs associated with unacceptable side effects such as infections, development of tumours and disruption of natural regulatory mechanisms.

Professor David Wraith, who led the research, said: “Insight into the molecular basis of antigen-specific immunotherapy opens up exciting new opportunities to enhance the selectivity of the approach while providing valuable markers with which to measure effective treatment. These findings have important implications for the many patients suffering from autoimmune conditions that are currently difficult to treat.”

This treatment approach, which could improve the lives of millions of people worldwide, is currently undergoing clinical development through biotechnology company Apitope, a spin-out from the University of Bristol.

Researchers publish first study of brain activation in MS using fNIRS

Using functional near infrared spectroscopy (fNIRS), Kessler Foundation researchers have shown differential brain activation patterns between people with multiple sclerosis (MS) and healthy controls. This is the first MS study in which brain activation was studied using fNIRS while participants performed a cognitive task. The article, “Neuroimaging and cognition using functional near infrared spectroscopy (fNIRS) in multiple sclerosis,” was published online on June 11 by Brain Imaging and Behavior. Authors are Jelena Stojanovic-Radic, PhD, Glenn Wylie, DPhil, Gerald Voelbel, PhD, Nancy Chiaravalloti, PhD, and John DeLuca, PhD.

Researchers compared 13 individuals with MS with 12 controls for their performance on a working memory task with four levels of difficulty. Most such studies have employed functional magnetic resonance imaging (fMRI); fNIRS has been used infrequently in clinical populations, and has not been applied previously to neuroimaging research in MS.  Studies comparing fMRI findings with those of fNIRS, however, show broad agreement in terms of activation patterns.

Results showed differences in activation between the groups that were dependent on task load. The MS group had an increase in activation at low task difficulty and a decrease in activation at high task difficulty. Conversely, in the control group, activation decreased with low task difficulty and increased with high task difficulty. Performance accuracy was lower in the MS group for low task load; there were no differences between the groups at the higher task loads.  

“The data we obtained via fNIRS are consistent with fMRI data for clinical populations. We demonstrated that fNIRS is capable of detecting neuronal activation with a reasonable degree of detail,” noted Glenn Wylie, DPhil, associate director of Neuroscience and the Neuroimaging Center at Kessler Foundation. “We attribute the differences in brain activation patterns to the effort expended during the working memory task rather than to differences in speed of processing,” he added. “Because fNIRS is more portable and easier to use that fMRI, it may offer advantages in monitoring cognitive interventions that require frequent scans.”

In addition to working memory, future research in clinical populations should focus on processing speed and episodic memory, cognitive functions that are also affected in MS.

(Image credit)

Wii Balance Board Induces Changes in the Brains of MS Patients

A balance board accessory for a popular video game console can help people with multiple sclerosis (MS) reduce their risk of accidental falls, according to new research published online in the journal Radiology. Magnetic resonance imaging (MRI) scans showed that use of the Nintendo Wii Balance Board system appears to induce favorable changes in brain connections associated with balance and movement.

Balance impairment is one of the most common and disabling symptoms of MS, a disease of the central nervous system in which the body’s immune system attacks the protective sheath around nerve fibers. Physical rehabilitation is often used to preserve balance, and one of the more promising new tools is the Wii Balance Board System, a battery-powered device about the size and shape of a bathroom scale. Users stand on the board and shift their weight as they follow the action on the television screen during games like slalom skiing.

While Wii balance board rehabilitation has been reported as effective in patients with MS, little is known about the underlying physiological basis for any improvements in balance.

Researchers recently used an MRI technique called diffusion tensor imaging (DTI) to study changes in the brains of 27 MS patients who underwent a 12-week intervention using Wii balance board-based visual feedback training. DTI is a non-conventional MRI technique that allows detailed analysis of the white matter tracts that transmit nervous signals through the brain and body.

MRI scans of the MS patients showed significant effects in nerve tracts that are important in balance and movement. The changes seen on MRI correlated with improvements in balance as measured by an assessment technique called posturography.

These brain changes in MS patients are likely a manifestation of neural plasticity, or the ability of the brain to adapt and form new connections throughout life, according to lead author Luca Prosperini, M.D., Ph.D., from Sapienza University in Rome, Italy.

"The most important finding in this study is that a task-oriented and repetitive training aimed at managing a specific symptom is highly effective and induces brain plasticity," he said. "More specifically, the improvements promoted by the Wii balance board can reduce the risk of accidental falls in patients with MS, thereby reducing the risk of fall-related comorbidities like trauma and fractures."

Dr. Prosperini noted that similar plasticity has been described in persons who play video games, but the exact mechanisms behind the phenomenon are still unknown. He hypothesized that changes can occur at the cellular level within the brain and may be related to myelination, the process of building the protective sheath around the nerves.

The rehabilitation-induced improvements did not persist after the patients discontinued the training protocol, Dr. Prosperini said, most likely because certain skills related to structural changes to the brain after an injury need to be maintained through training.

"This finding should have an important impact on the rehabilitation process of patients, suggesting that they need ongoing exercises to maintain good performance in daily living activities," Dr. Prosperini said.