Posts tagged demyelination
Articles and news from the latest research reports.
(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.”
There’s Life After Radiation for Brain Cells
Johns Hopkins researchers suggest neural stem cells may regenerate after anti-cancer treatment
Scientists have long believed that healthy brain cells, once damaged by radiation designed to kill brain tumors, cannot regenerate. But new Johns Hopkins research in mice suggests that neural stem cells, the body’s source of new brain cells, are resistant to radiation, and can be roused from a hibernation-like state to reproduce and generate new cells able to migrate, replace injured cells and potentially restore lost function.
“Despite being hit hard by radiation, it turns out that neural stem cells are like the special forces, on standby waiting to be activated,” says Alfredo Quiñones-Hinojosa, M.D., a professor of neurosurgery at the Johns Hopkins University School of Medicine and leader of a study described online today in the journal Stem Cells. “Now we might figure out how to unleash the potential of these stem cells to repair human brain damage.”
The findings, Quiñones-Hinojosa adds, may have implications not only for brain cancer patients, but also for people with progressive neurological diseases such as multiple sclerosis (MS) and Parkinson’s disease (PD), in which cognitive functions worsen as the brain suffers permanent damage over time.
In Quiñones-Hinojosa’s laboratory, the researchers examined the impact of radiation on mouse neural stem cells by testing the rodents’ responses to a subsequent brain injury. To do the experiment, the researchers used a device invented and used only at Johns Hopkins that accurately simulates localized radiation used in human cancer therapy. Other techniques, the researchers say, use too much radiation to precisely mimic the clinical experience of brain cancer patients.
In the weeks after radiation, the researchers injected the mice with lysolecithin, a substance that caused brain damage by inducing a demyelinating brain lesion, much like that present in MS. They found that neural stem cells within the irradiated subventricular zone of the brain generated new cells, which rushed to the damaged site to rescue newly injured cells. A month later, the new cells had incorporated into the demyelinated area where new myelin, the protein insulation that protects nerves, was being produced.
“These mice have brain damage, but that doesn’t mean it’s irreparable,” Quiñones-Hinojosa says. “This research is like detective work. We’re putting a lot of different clues together. This is another tiny piece of the puzzle. The brain has some innate capabilities to regenerate and we hope there is a way to take advantage of them. If we can let loose this potential in humans, we may be able to help them recover from radiation therapy, strokes, brain trauma, you name it.”
His findings may not be all good news, however. Neural stem cells have been linked to brain tumor development, Quiñones-Hinojosa cautions. The radiation resistance his experiments uncovered, he says, could explain why glioblastoma, the deadliest and most aggressive form of brain cancer, is so hard to treat with radiation.
(Source: hopkinsmedicine.org)
Zebrafish study paves the way for new treatments for genetic disorder
Scientists from the University of Sheffield have paved the way for new treatments for a common genetic disorder thanks to pioneering research on zebrafish – an animal capable of mending its own heart.
Charcot Marie Tooth disease (CMT) is the most common genetic disorder affecting the nervous system. More than 20,000 people in the UK suffer from CMT, which typically causes progressive weakness and long-term pain in the feet, leading to walking difficulties. There is currently no cure for CMT.
A research project conducted at the Sheffield Institute for Translational Neuroscience (SITraN) and the MRC Centre for Developmental and Biomedical Genetics (CDBG) by Dr Andrew Grierson and his team has revealed that zebrafish could hold the key to finding new therapeutic approaches to treat the condition.
Dr Grierson said: “We have studied zebrafish with a genetic defect that causes CMT in humans. The fish develop normally, but once they reach adulthood they start to develop difficulties swimming.
"By looking at the muscles of these fish we have discovered that the problem lies with the connections between motor neurons and muscle, which are known to be essential for walking in humans and also swimming in fish."
CMT represents a group of neurodegenerative disorders typically characterised by demyelination (CMT1), a process which causes damage to the myelin sheaths that surround our neurons, or distal axon degeneration (CMT2) of motor and sensory neurons. The distal axon is the terminal where neurotransmitter packages within neurons are docked.
The majority of CMT2 cases are caused by mutations in mitofusin 2 (MFN2), which is an essential gene encoding a protein responsible for fusion of the mitochondrial outer membrane. Mitochondria are known as the cellular power plants because they generate most of the supply of adenosine triphosphate (ATP), which is used as a source of chemical energy.
Dr Grierson said: “Previous work on this disorder using mammalian models such as mice has been problematic, because the mitofusin genes are essential for embryonic development. Using zebrafish we were able to develop a model with an adult onset, progressive phenotype with predominant symptoms of motor dysfunction similar to CMT2.
"Motor neurons are the largest cells in our bodies, and as such they are highly dependent on a cellular transport system to deliver molecules through the long nerve cell processes which connect the spinal cord to our muscles. We already know that defects in the cellular transport system occur early in the development of diseases such as Alzheimer’s disease, Motor Neuron Disease and spastic paraplegia. Using our zebrafish model we have found that similar defects in transport are also a key part of the disease process in CMT."
Dr Grierson and his team are now seeking funding to identify new treatments for CMT using the zebrafish model. Because of their size and unique biology, zebrafish are ideal to be used in drug screens for the identification of new therapies for untreatable human conditions.
(Image courtesy: University College London)
Absence of Gene Leads to Earlier, More Severe Case of Multiple Sclerosis
A UC San Francisco-led research team has identified the likely genetic mechanism that causes some patients with multiple sclerosis (MS) to progress more quickly than others to a debilitating stage of the disease. This finding could lead to the development of a test to help physicians tailor treatments for MS patients.
Researchers found that the absence of the gene Tob1 in CD4+ T cells, a type of immune cell, was the key to early onset of more serious disease in an animal model of MS.
Senior author Sergio Baranzini, PhD, a UCSF associate professor of neurology, said the potential development of a test for the gene could predict the course of MS in individual patients.
The study, done in collaboration with UCSF neurology researchers Scott Zamvil, MD, and Jorge Oksenberg, PhD, was published on June 24 in the Journal of Experimental Medicine.
MS is an inflammatory disease in which the protective myelin sheathing that coats nerve fibers in the brain and spinal cord is damaged and ultimately stripped away – a process known as demyelination. During the highly variable course of the disease, a wide range of cognitive, debilitating and painful neurological symptoms can result.
In previously published work, Baranzini and his research team found that patients at an early stage of MS, known as clinically isolated syndrome, who expressed low amounts of Tob1 were more likely to exhibit further signs of disease activity – a condition known as relapsing-remitting multiple sclerosis – earlier than those who expressed normal levels of the gene.
The current study, according to Baranzini, had two goals: to recapitulate in an animal model what the researchers had observed in humans, and uncover the potential mechanism by which it occurs.
The authors were successful on both counts. They found that when an MS-like disease was induced in mice genetically engineered to be deficient in Tob1, the mice had significantly earlier onset compared with wild-type mice, and developed a more aggressive form of the disease.
Subsequent experiments revealed the probable cause: the absence of Tob1 in just CD4+ T cells. The scientists demonstrated this by transferring T cells lacking the Tob1 gene into mice that had no immune systems but had normal Tob1 in all other cells. They found that the mice developed earlier and more severe disease than mice that had normal Tob1 expression in all cells including CD4+.
“This shows that Tob1 only needs to be absent in this one type of immune cell in order to reproduce our initial observations in mice lacking Tob1 in all of their cells,” said Baranzini.
Personalized Treatments for MS Patients
The researchers also found the likely mechanism of disease progression in the Tob1-deficient mice: higher levels of Th1 and Th17 cells, which cause an inflammatory response against myelin, and lower levels of Treg cells, which normally regulate inflammatory responses. The inflammation results in demyelination.
The research is significant for humans, said Baranzini, because the presence or absence of Tob1 in CD4+ cells could eventually serve as a prognostic biomarker that could help clinicians predict the course and severity of MS in individual patients. “This would be useful and important,” he said, “because physicians could decide to switch or modify therapies if they know whether the patient is likely to have an aggressive course of disease, or a more benign course.”
Ultimately, predicted Baranzini, “This may become an example of personalized medicine. When the patient comes to the clinic, we will be able to tailor the therapy based on what the tests tell us. We’re now laying the groundwork for this to happen.”
(Source: ucsf.edu)
OHSU researchers discover how enzyme may prevent nervous system repair in multiple sclerosis
Discovery could be ‘life-changer’ for millions with MS, stroke and other conditions that cause brain damage
Researchers at Oregon Health & Science University have discovered that blocking a certain enzyme in the brain can help repair the brain damage associated with multiple sclerosis and a range of other neurological disorders.
The discovery could have major implications for multiple sclerosis, complications from premature birth and other disorders and diseases caused by demyelination – a process where the insulation-like sheath surrounding nerve cells in the brain becomes damaged or destroyed. Demyelination disrupts the ability of nerve cells to communicate with each other, and produces a range of motor, sensory and cognitive problems in MS and other disorders.
The study was published this week in the online edition of the Annals of Neurology. The study was conducted by a team of researchers led by Larry Sherman, Ph.D., who is a professor of cell and development biology at OHSU and a senior scientist in the Division of Neuroscience at the Oregon National Primate Research Center.
"What this means is that we have identified a whole new target for drugs that might promote repair of the damaged brain in any disorder in which demyelination occurs," Sherman said. "Any kind of therapy that can promote remyelination could be an absolute life-changer for the millions of people suffering from MS and other related disorders."