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New study unravels how myelin is repaired(07/09/15)

Japanese scientists have discovered new information about how the myelin sheath is repaired following damage.

The study, titled “Inactivation of Protein Tyrosine Phosphatase Receptor Type Z by Pleiotrophin Promotes Remyelination through Activation of Differentiation of Oligodendrocyte Precursor Cells,” appeared in the Journal of Neuroscience on September 2, 2015.

The symptoms of multiple sclerosis are due to an immune attack on the body’s own myelin. When myelin is lost around nerve cells, this can cause unpredictable loss of movement, sensation, vision problems and feelings of pain. Myelin is made by special nervous system cells called oligodendrocytes. Although it is well-known that myelin can be repaired by oligodendrocytes if it is damaged scientists do not understand the exact repair mechanisms used by these cells. In MS, myelin unfortunately does not appear to be easily repaired, also for unknown reasons.

The researchers, led by Professor Masaharu Noda and colleagues of the National Institute for Basic Biology, wanted to study how myelin is repaired in mice with an experimental form of MS, induced by the myelin-damaging drug cuprizone. They studied both normal mice and genetically-altered mice that lacked protein tyrosine phosphatase receptor type Z (PTPRZ), which is a protein that may cause oligodendrocytes to turn into mature cells, rather than stay in a more immature stage.

Following loss of myelin with cuprizone, the mice that lacked PTPRZ had more myelin repair than the normal mice. The researchers also found that a protein called pleiotrophin (PTN), seemed to be associated with remyelination in the mouse brains, suggesting that it may inactivate PTPRZ. When studied in vitro (in a dish), oligodendrocytes treated with PTN turned into a form that creates new myelin.

Overall, the study suggests that pleiotrophin is secreted by nerve cells when they are damaged and lose myelin, and pleiotrophin then inhibits PTPRZ. This allows oligodendrocytes to create new myelin.

The new understanding of how myelin is formed could provide the basis for new MS treatments, for example, drugs that inhibit PTPRZ or that increase pleiotrophin might be used in the future. Of course, much more research is needed and the investigators will need to find new compounds that act on PTPRZ.

According to Noda “This achievement was made possible by establishing oligodendrocyte precursor cell lines. Pleiotrophin is an endogenous PTPRZ inhibitor, but if synthetic PTPRZ inhibitors were obtained, then effective treatments for multiple sclerosis should become possible. We are currently directing our research in that direction.”

Source: Multiple Sclerosis News Today © BioNews Services 2015 (07/09/15)

Guanabenz studies underway(05/05/15)

The Myelin Repair Foundation (MRF), in partnership with the National Institutes of Health (NIH) has announced patients are now being enrolled in a clinical trial to study guanabenz, an FDA-approved drug to treat high blood pressure that was identified by MRF-funded researchers as a potential therapy to reduce loss of myelin in multiple sclerosis patients.

If successful, guanabenz (formerly called MRF-008) could be the first MS treatment to focus on protecting myelin from damage, which is the hallmark of MS, rather than on suppressing the immune system - as all currently available MS treatments do.

The trial, a collaboration between the MRF and the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (NIH) Clinical Centre, is being led by NIH Investigators Dr. Irene Cortese, M.D., and Dr. Daniel Reich, M.D., Ph.D.

Myelin is the membrane that surrounds and protects nerve fibres (axons) in the central nervous system.

In MS patients, the immune system damages myelin and the cells that produce and maintain it (oligodendrocytes). As the disease progresses, severe myelin degeneration is accompanied by axonal loss and neurodegeneration, all of which can profoundly disrupt signalling in the central nervous system and so leading to the array of symptoms that characterises MS.

Because loss of myelin correlates with neurodegeneration, new therapies that are designed to protect myelin or promote remyelination would be categorized as neuroprotective.

In a Nature Communications paper published in March, MRF-funded researchers reported that guanabenz prevents myelin loss and alleviates clinical symptoms of MS in animal models by prolonging an innate mechanism that is activated in response to stressors such as inflammation.

When this protective response is disrupted or overloaded - by the chronic inflammation seen in MS, for example - oligodendrocyte cell death and demyelination are significantly enhanced. Treatment with guanabenz strengthens this stress-response mechanism and helps protect oligodendrocytes from cell death. These findings point to promising avenues for the development of new treatments for MS.

"Guanabenz appears to enhance the cell's own protective machinery to diminish the loss of myelin," said senior study author Brian Popko, Ph.D., Jack Miller Professor of Neurological Disorders at the University of Chicago and a member of the Myelin Repair Foundation's Research Consortium.

"While there have been many efforts to stimulate remyelination, this now represents a unique protective approach. You don't have to repair the myelin if you don't lose it in the first place."

The MRF has supported Dr. Popko's research on the effects of inflammation on oligodendrocyte health and myelin production for more than ten years. In addition to Dr. Popko's team at the University of Chicago, MRF-funded researchers at Northwestern University in Chicago, Case-Western Reserve University in Cleveland, and scientists at the MRF's Translational Medicine Center in Sunnyvale, CA, made key contributions to the guanabenz publication.

The MRF's clinical advisory board reviewed the preclinical data and encouraged the MRF to advance guanabenz into clinical testing. The drug's protective efficacy and ability to alleviate myelin loss, coupled with its existing FDA approval and good safety profile, makes the clinical implications promising for MS patients, the advisory board concluded. However, before clinical studies could be initiated, the MRF had to identify a contract drug manufacturer to make clinical-grade guanabenz.

Because guanabenz has been off the market for many years, it is no longer manufactured anywhere in the world.

"We are very pleased guanabenz is now moving into studies in MS patients," said Tassie Collins, Ph.D., Vice President of Translational Medicine at the Myelin Repair Foundation.

"This is a promising approach, but it might not have been able to move forward without MRF's participation."

Because it is a generic drug, guanabenz would be an unlikely investment choice for pharmaceutical companies. And because it had to be custom-manufactured for the trial, most academic organizations would have been unable to resource it.

Source: Drug Research Drug Discovery & Development © PBR 2015 (05/05/15)

Remyelinating antibody study data revealed(23/04/15)

Acorda Therapeutics Inc has presented data from a Phase 1 clinical trial of rHIgM22, a remyelinating antibody being studied for the treatment of multiple sclerosis.

Safety data showed rHIgM22 was well-tolerated in each of the five tested doses, supporting additional clinical development. In addition, testing detected rHIgM22 in cerebrospinal fluid (CSF), indicating the drug’s access to the central nervous system.

These data were presented at the 67th American Academy of Neurology Annual Meeting in Washington, DC.

“In this study, rHIgM22 was well-tolerated over the full range of dose levels tested. Furthermore, we were able to verify that rHIgM22 is present in the CSF, showing that the antibody is available to the brain,” said Anthony Caggiano, M.D., Ph.D., Acorda’s Senior Vice President of Research and Development.

“We plan to advance our clinical program based on this data. The next study will include patients experiencing acute relapses. The combined results of these two studies will inform subsequent trials, which we anticipate will enrol both stable patients and those experiencing active relapses.”

This was a placebo-controlled, single-dose, escalating study in 72 patients with clinically stable MS to explore dose tolerability for six months after treatment. rHIgM22 was well-tolerated at all doses tested, with no safety signals identified. There were no dose-limiting toxicities and no serious adverse events in any of the five rHIgM22 dose levels in the study. The data presented included the concentration of rHIgM22 in the CSF at two days and four weeks after IV infusion. The antibody was measured at levels expected for antibodies of this class. There were no significant changes from baseline in clinical measures including MRI, magnetic resonance spectroscopy, Expanded Disability Status Scale, Timed 25-Foot Walk, and low contrast visual acuity.

The most commonly observed adverse events (>5% in the combined rHIgM22 treatment groups) reported in the study were: headache, contact dermatitis, multiple sclerosis relapse, infusion site hematoma, fatigue, arthralgia, back pain, muscular weakness, neck pain, pain in an extremity, pruritus, contusion, and flushing. No participants withdrew due to adverse events. No safety signals were identified by standard clinical MRI evaluations, or standard clinical, laboratory or ECG assessments.

Source: Finances © 2014 Finances International Ltd (23/04/15)

Blood pressure drug protects against symptoms of MS in animal models(13/03/15)

An FDA-approved drug for high blood pressure, guanabenz, prevents myelin loss and alleviates clinical symptoms of multiple sclerosis (MS) in animal models, according to a new study at the University of Chicago in Nature Communications. The drug appears to enhance an innate cellular mechanism that protects myelin-producing cells against inflammatory stress.

"Guanabenz appears to enhance the cell's own protective machinery to diminish the loss of myelin, which is the major hallmark of MS," said senior study author Brian Popko, PhD, Jack Miller Professor of Neurological Disorders at the University of Chicago "While there have been many efforts to stimulate re-myelination, this now represents a unique protective approach. You don't have to repair the myelin if you don't lose it in the first place."

Multiple sclerosis is characterized by an abnormal immune response that leads to inflammation in the brain and the destruction of myelin - a fatty sheath that protects and insulates nerve fibers. MS is thought to affect more than 2.3 million people worldwide and has no known cure.

Popko and his colleagues have previously shown that oligodendrocytes, the brain cells which produce myelin, possess an innate mechanism that responds to stressors such as inflammation. It temporarily shuts down almost all normal protein production in the cell and selectively increases the production of protective proteins. When this mechanism is malfunctioning or overloaded - by the chronic inflammation seen in MS, for example - oligodendrocyte death and demyelination is significantly increased.

A recent study found evidence that guanabenz, a drug approved for oral administration for hypertension, enhances this stress response pathway independent of its anti-hypertension actions. To test the suitability of guanabenz as a potential treatment for MS, Popko and his team exposed cultured oligodendrocyte cells to interferon gamma - a molecule that increases inflammation - resulting in greatly increased myelin loss and cell death.

Treating these cells with guanabenz prevented myelin loss and restored cell survival to near normal levels. Oligodendrocytes that were not exposed to interferon gamma were unaffected by guanabenz, suggesting that it enhances only an active stress response pathway.

The team then tested the drug on multiple mouse models of MS. When treated with guanabenz, mice that are genetically engineered to express high amounts of interferon gamma in their brains were protected against oligodendrocyte and myelin loss. Treated mice retained several times more myelination and oligodendrocytes than untreated mice.

To study a chronic model of MS, the researchers immunized mice with a component of myelin, triggering an immune response against myelin similar to MS in humans. Clinical symptoms developed, but guanabenz administered a week after immunization significantly delayed the onset of these symptoms and reduced peak severity. Treatment also prevented around 20 percent of mice from developing symptoms at all.

To study the suitability of guanabenz as a therapeutic after MS symptoms have already appeared and peaked, the researchers used a mouse model in which symptoms relapse and remit - cycling from high severity to low severity to high again over time. They administered guanabenz immediately after symptoms peaked, and found a nearly 50 percent reduction in severity during the next relapse cycle.

"Human MS predominantly follows a relapsing-remitting pattern," said co-author Sharon Way, PhD, a National MS Society Postdoctoral Fellow at the University of Chicago. "Our hope is that this approach would provide protection against future relapses by making them milder and less frequent."

The team confirmed that guanabenz acts by temporarily blocking the reactivation of a protein known as eukaryotic translation initiation factor 2 (eIF2α). When deactivated, eIF2α initiates the stress response pathway. Blocking its reactivation results in a prolonged stress response and provides protection against cell death. The researchers hypothesize that guanabenz stimulates a protective cascade - because fewer oligodendrocytes die, less immune cells are recruited to the brain, which results in a decreased inflammatory response and preservation of myelin levels.

The Myelin Repair Foundation, which funded this work as part of a multi-institutional effort to accelerate research and development of treatments for MS, has entered into a cooperative agreement with the National Institutes of Health to assess guanabenz as a therapeutic candidate in MS clinical studies.

"Guanabenz will probably not be a standalone drug, but we hope that it can be developed for use in combination with other medications," Popko said. "Some current treatments can have severe side effects - for example dangerous infections in the brain. It would be of tremendous benefit for patients to have effective, less-risky therapies.

Source: MedicalXpress © Medical Xpress 2011-2014, Science X network (13/03/15)

FDA-approved drug ‘boosts myelin synthesis’(02/03/15)

The Journal of Neuroscience is reporting that a University at Buffalo researcher has discovered a way to keep remyelination going, using a drug that's already on the market.

According to scientists, there is a brief period after the myelin sheath has been attacked and damaged when it is able to repair itself, but this doesn’t last and the damage deteriorates further as someone with MS ages and their condition progresses.

“We have identified a new drug target that promotes stem cell therapy for myelin-based conditions such as MS,” says lead author Fraser J. Sim, PhD, assistant professor in the Department of Pharmacology and Toxicology in the University at Buffalo School of Medicine and Biomedical Sciences.

The study shows it is possible to boost myelination by targeting human oligodendrocyte progenitor cells with solifenacin, an anti-muscarinic drug that currently is approved and marketed to treat overactive bladder.

“Our hypothesis is that in MS, the oligodendrocyte progenitor cells seem to get stuck,” Sim explains. “When these cells don't mature properly, they don't differentiate into myelinating oligodendrocytes.”

In the new study, the approach Sim and his colleagues took was to first characterise the molecular pathways that govern the differentiation of human oligodendrocyte progenitor cells, and then identify drug candidates that would promote differentiation and myelin production.

They found that when a muscarinic type 3 receptor on human oligodendrocyte progenitor cells was activated, differentiation was completely blocked.

“So we thought, if we had something that blocks instead of activates this receptor, could we boost differentiation?” said Fraser. To do that, the researchers turned to solifenacin, the anti-muscarinic drug for overactive bladder; the bladder muscle contains several muscarinic receptors.

“We were excited about this because solifenacin is an approved drug that's already on the market,” said Sim.

To test whether the drug could boost myelin synthesis, the researchers transplanted human oligodendrocyte progenitor cells into mice that could not make myelin. The result was increased differentiation and myelin synthesis from the transplanted human cells.

However, Sim and his colleagues needed a functional endpoint, a way to know that the myelin being made was being translated into improved behaviour or function.

So Sim teamed up with Richard J. Salvi, PhD, SUNY Distinguished Professor in the Department of Communicative Disorders and Sciences, and director of UB's Center for Hearing and Deafness.

Together, they determined that an auditory brainstem response, which records brain wave activity in response to sounds, would be appropriate.

Sim said that it takes a certain amount of time for a signal to go from the ear to the front of the brain: “So in the readout, you get waves that should have a certain time pattern. When there isn't enough myelin, the signalling slows down. And if you add myelin, you should see the signals speed up.”

The tests showed improvement in the response to auditory signals in animals transplanted with the human oligodendrocyte progenitor cells treated with solifenacin.

“We have identified a way to improve human myelination,” said Sim.

The promising results have prompted Sim and his colleagues to seek funding for a small human trial. The study results are all preclinical and no human testing has been done yet.

The current study was funded by America’s National Multiple Sclerosis Society, the Kalec Multiple Sclerosis Foundation and the Empire State Stem Cell Fund.

In addition to Sim and Salvi, other co-authors are Kavitha Abiraman, Suyog U. Pol, Melanie A. O'Bara, Guang-Di Chen, Zainab Khaku, Jing Wang, David Thorn, Bansi H. Vedia, Exinne C. Ekwegbalu and Jun-Xu Li.

The new study adds to Sim's body of research on stem cells and myelination, which previously determined that a critical phase of remyelination fades with age.

Source: Medical Xpress © Medical Xpress 2011-2014, Science X network (02/03/15)

Possible novel therapy for Multiple Sclerosis discovered(14/01/15)

Semaphorin 4D (SEMA4D) is a viable target for therapy in neuroinflammatory and neurodegenerative diseases like multiple sclerosis (MS), according to findings published in Neurobiology of Disease.

Researchers from Vaccinex, Inc. in Rochester, New York conducted a study of mouse models of experimental autoimmune encephalomyelitis (EAE) – a surrogate for human MS – in order to determine if SEMA4D or any specific novel molecular therapy would make a viable target. The investigators created a monoclonal antibody which binds animal model SEMA4D with high affinity and inhibits the binding between SEMA4D and its receptors. In the process, anti SEMA4D binds in vitro to the recombinant SEMA4D, which prohibited the survival and differentiation of oligodendrocytes precursor cells (OPCs) – important for maintaining the myelin coating on neurons. The EAE rodents demonstrated anti SEMA4D significantly inhibited the development of the neurodegenerative diseases by preserving the BBB integrity and axonal myelination.

A further result the researchers noted was that anti SEMA4D tended to aid the migration of OPC to the site of lesions and improved myelin status after inducing demyelination chemically.

The researchers found that in 3 causes of neuroinflammatory disease, which included the breakdown of the brain blood barrier (BBB), apoptosis of OPCs, and activation of microglia, SEMA4D was effective in blocking the activity. Antibodies were vital to this blocking process, the researchers found.

Vaccinex is currently testing an antibody that blocks human SEMA4D called VX15/2503 in a phase 1 clinical trial. That study is designed to test the safety and tolerability in human patients with MS. The results of this study are expected to be available in early 2015. Vaccinex is a clinical stage biotechnology company which focuses on the discovery and development of human therapeutic monoclonal antibodies to treat cancer and neurodegenerative diseases such as MS and Huntington’s disease.

Source: HCP Live © HCP Live 2015 (14/01/15)

University of Edinburgh and Genzyme collaboration aims to reduce neurodegeneration in MS(09/01/15)

University of Edinburgh scientists are set to work with leading biotechnology company Genzyme, a Sanofi company, to carry out drug discovery research that could reduce neuron damage in the brain.

The collaboration - facilitated by Edinburgh BioQuarter's Business Development team - will focus on identifying therapeutic candidates capable of promoting remyelination and reducing neurodegeneration, mostly in relation to Multiple Sclerosis (MS).

MS is caused by damage to myelin, the protective layer that surrounds nerve fibres. This damage affects the transmission of electrical signals from the brain to the rest of the body and results in symptoms such as problems with muscle movement, balance and vision. Over time MS patients accrue disability, which usually slowly gets worse - this is related to neurodegeneration.

A natural process called 'remyelination' can repair damaged myelin and restore nerve function. In MS, however, remyelination is inefficient.

Scientists from the University of Edinburgh have discovered a physiologically-occurring molecule that prevents the cells needed to help repair damaged myelin from reaching the area of damage, which limits remyelination.

By working with Genzyme, co-investigators Dr Anna Williams, of the MRC Centre for Regenerative Medicine, and Dr Scott Webster hope to identify inhibitors of this molecule (or its receptor) to prevent this block and encourage the cells capable of repairing myelin into the area of damage.

Dr. Williams said: "If successful, this will be a step-change in MS treatment as current treatments are unable to repair the damaged neurons that cause the symptoms of MS.

"Ultimately this could reduce neurodegeneration in MS and the accumulation of disability in patients. This treatment could also be used in other diseases where myelin is damaged, such as spinal cord injury."

Dr. Johanne Kaplan, Vice President of Neuroimmunology Research at Genzyme, stated: "We are very much looking forward to a productive collaboration with Drs. Williams and Webster based on our combined expertise in remyelination and drug discovery and development. Remyelination-promoting therapies remain an unmet need and would be of great benefit to MS patients".

Source: MNT © MediLexicon International Ltd 2004-2015 (09/01/15)

The effects of age on remyelination in MS are reversible(03/10/14)

Like conducting an errant orchestra to play together, researchers are guiding processes that go awry in multiple sclerosis to repair themselves.

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."

Source: Medical Xpress © Medical Xpress 2011-2014, Science X network (03/10/14)

Olfactory dysfunction is common in multiple sclerosis (22/09/14)

Olfactory Pathology in Central Nervous System Demyelinating Diseases.

DeLuca GC, Joseph A, George J, Yates RL, Hamard M, Hofer M, Esiri MM.


Olfactory dysfunction is common in multiple sclerosis (MS). Olfactory bulb and tract pathology in MS and other demyelinating disease remains unexplored.

A human autopsy cohort of pathologically confirmed cases encompassing the spectrum of demyelinating disease (MS; n=17), neuromyelitis optica (NMO); n=3), and acute disseminated encephalomyelitis (ADEM); n=7)) was compared to neuroinflammatory (herpes simplex virus encephalitis (HSE); n=3), neurodegenerative (Alzheimer's disease (AD); n=4), and non-neurologic (n=8) controls.

For each case, olfactory bulbs and/or tracts were stained for myelin, axons, and inflammation. Inferofrontal cortex and hippocampus were stained for myelin in a subset of MS and ADEM cases.

Olfactory bulb/tract demyelination was frequent in all demyelinating diseases (MS 12/17 (70.6%); ADEM 3/7 (42.9%); NMO 2/3 (66.7%)) but was absent in HSE, AD, and non-neurologic controls.

Inflammation was greater in the demyelinating diseases compared to non-neurologic controls.

Olfactory bulb/tract axonal loss was most severe in MS where it correlated significantly with the extent of demyelination (r=0.610, P=0.009) and parenchymal inflammation (r=0.681, P=0.003).

The extent of olfactory bulb/tract demyelination correlated with that found in the subjacent adjacent inferofrontal cortex but not hippocampus.

We provide unequivocal evidence that olfactory bulb/tract demyelination is frequent, can occur early and be highly inflammatory, and is specific to demyelinating disease.

Source: Brain Pathol. 2014 Sep 17. doi: 10.1111/bpa.12209. [Epub ahead of print] & Pubmed PMID: 25230202 (22/09/14)

Myelin measure in MS tracks patient disability(12/09/14)

Whole-brain measures of myelin water fraction (MWF) -- reflecting the amount of myelin present in brain tissue -- correlated significantly with disease duration and disability levels in multiple sclerosis, supporting a role for MWF in patient management and as an outcome in clinical trials, a researcher said here.

In a cross-sectional study of 141 MS patients and 10 neurologically healthy controls, the "skew" of one of two peaks seen in the distribution of MWF across the brain, including normal-appearing white matter as well in MS-type lesions, was associated with Expanded Disability Status Scale (EDSS) score (P=0.000039) and with the number of years since symptom onset (P=0.012), said Elizabeth Monohan, of Weill Cornell Medical College in New York City.

"To date, our study is the first to demonstrate an approach to modeling white matter myelin water fraction to explore clinical variables that may be driving myelin content," she said at the European Committee for Treatment and Research in Multiple Sclerosis annual meeting, held jointly this year with its North American counterpart.

"These observations promote the use of myelin water fraction as a biomarker for myelin," she added, noting that the relationship between MWF on the one hand and EDSS and disease duration on the other suggests that "myelin loss is accumulated during the disease and perhaps contributes to the progressive nature of MS."

Demyelination is the chief pathology in MS and is believed to be the driving force behind the physical disabilities that mark the disease in its later stages. Nerve fibers are sheathed in a protective layer of proteins dominated by myelin; its progressive loss leaves nerve axons vulnerable to various insults such that eventually they break down, leading to loss of nerve function.

However, this process has been impossible to witness or measure directly in human patients. Recently, MWF -- measurable with MRI scans as the amount of water within myelin versus the total amount of water in the tissue scanned -- has emerged as a quantitative marker of myelin that can be assessed noninvasively in living patients.

Up till now, though, its clinical applicability has been uncertain, Monohan explained, because it was unclear whether focusing on MWF in lesioned areas was sufficient and also because the scans took a long time to perform and data analysis was difficult.

She said her group had developed a more practical approach to the scans that cut the image acquisition time to just 10 minutes for the whole brain. Moreover, she and her colleagues determined that scanning the whole brain was the right way to go, because there was no solid evidence to indicate that the clinically relevant demyelination occurs only in lesions.

The whole-brain MWF measurement, Monohan said, provides an "unbiased approach" for studying myelin dynamics.

An important finding in the study was that patients showed a "bimodal" distribution in histograms of MWF values -- a small spike in relatively low values and another larger spike in mid-range values. Monohan said that 94% of the patients showed this type of pattern, compared with just one of the 10 controls.

It was the shape of this spike in low values -- primarily the skew, but also its width -- that was most strongly correlated with EDSS and disease duration, she reported. The shape of the larger mid-value spike was associated with EDSS score but not disease duration.

Monohan said her group is pursuing additional studies to look at a broader patient population, with a wider range of EDSS scores and disease durations. Another goal is to examine MWF in patients undergoing treatment with current MS drugs.

Also, longitudinal studies to track within-patient changes in MWF over time will be necessary to determine how it may correlate with lesion evolution and, importantly, disease progression.

The study was funded by the National Multiple Sclerosis Society and the National Institutes of Health.

Study investigators had relationships with Biogen Idec, Teva, Questcor, Genzyme, EMD Serono, Novartis, and Acorda.

Primary source: ECTRIMS-ACTRIMS
Source reference: Monohan E, et al "Clinical disease burden predicts myelin water fraction in multiple sclerosis" ECTRIMS-ACTRIMS 2014; Abstract YI1.3.

Source: Medpage Today © 2014 MedPage Today, LLC. (12/09/14)

People with multiple sclerosis lose myelin in grey matter(10/09/14)

People with multiple sclerosis (MS) lose myelin in the grey 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 fibres, 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 grey matter, the brain's information processing center that is made up primarily of nerve cell bodies. Though the myelin content in grey matter is small, it is still extremely important to proper function, as it enables protection of thin nerve fibers connecting neighbouring 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 grey matter has been proven by earlier post-mortem pathological studies," he said. "However, the clinical significance of the myelin loss, or demyelination, in grey 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 grey 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 utilises 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 grey 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, grey matter and MS lesions. The researchers further compared the results of their imaging technique with clinical tests characterising neurological dysfunction in MS patients.

The results showed that MPF was significantly lower in both white and grey 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 grey matter. MPF in brain tissues of MS patients significantly correlated with clinical disability and the strongest associations were found for grey matter.

"The major finding of the study is that the loss of myelin in grey matter caused by MS in its relative amount is comparable to or even larger than that in white matter," said Dr. Yarnykh. "Furthermore, grey 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 grey 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 grey 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."

Source: News-Medical.Net Copyright 2000-2014 AZoM.com Limited (10/09/14)