Category: Multiple Sclerosis

Physician-scientists at Oregon Health & Science University Doernbecher Children's Hospital have demonstrated for the first time that banked human neural stem cells — HuCNS-SCs, a proprietary product of StemCells Inc. — can survive and make functional myelin in mice with severe symptoms of myelin loss. Myelin is the critical fatty insulation, or sheath, surrounding new nerve fibers and is essential for normal brain function.

This is a very important finding in terms of advancing stem cell therapy to patients, the investigators report, because in most cases, patients are not diagnosed with a myelin disease until they begin to show symptoms. The research is published online in the journal Science Translational Medicine.

Myelin disorders are a common, extremely disabling, often fatal type of brain disease found in children and adults. They include cerebral palsy in children born prematurely as well as multiple sclerosis, among others.

Using advanced MRI technology, researchers at OHSU Doernbecher Children's Hospital also recently recognized the importance of healthy brain white matter at all stages of life and showed that a major part of memory decline in aging occurs due to widespread changes in the white matter, which results in damaged myelin and progressive senility (Annals of Neurology, September 2011).

In this breakthrough study, Stephen A. Back, M.D., Ph.D., senior author and clinician-scientist in the Papé Family Pediatric Research Institute at OHSU Doernbecher Children's Hospital, used a transgenic mouse model (Shiverer-immunodeficient) that develops progressive neurological deterioration because it is unable to make a key protein required to make normal myelin. Although this mouse has been widely investigated, prior to this study, true human brain-derived stem cells had not been tested for their potential to make new myelin in animals that were already deteriorating neurologically.

"Typically, newborn mice have been studied by other investigators because stem cells survive very well in the newborn brain. We, in fact, found that the stem cells preferentially matured into myelin-forming cells as opposed to other types of brain cells in both newborn mice and older mice. The brain-derived stem cells appeared to be picking up on cues in the white matter that instructed the cells to become myelin-forming cells," explained Back.

Although Back, in collaboration with investigators at StemCells Inc., had achieved success implanting stem cells in presymptomatic newborn animals, it was unclear whether the cells would survive after transplant into older animals that were already declining in health. Back and his colleagues put these cells to the test by transplanting them in animals that were declining neurologically and found that the stem cells were able to effectively survive and make functional myelin.

The study also is important because the research team was able to confirm by MRI that new myelin had been made by the stem cells within weeks after the transplant. Until now, it was unclear whether stem cell-derived myelin could be detected without major modifications to the stem cells, such as filling them with special dyes or iron particles that can be detected by the MRI.

These studies were particularly challenging, Back explained, because the mice were too sick to survive in the MRI scanner. Fortunately, OHSU is home to a leading national center for ultra-high field MRI scanners that were used to detect the myelin made by normal, unmodified stem cells.

"This is an important advance because it provides proof of principle that MRI can be used to track the transplants as myelin is being made. We actually confirmed that the MRI signal in the white matter was coming from human myelin made by the stem cells," Back said.

In a study conducted by clinical researchers at the University of California San Francisco and published in the same online issue of Science Translational Medicine (Gupta et. al), the human neural stem cells were also tested in a small number of patients with a rare childhood myelin disorder where the MRI was detecting signals from the brain consistent with myelin formation. Before MRI, there wasn't a way to confirm new myelin without a brain biopsy or an autopsy. The USCF researchers report the study results strongly support that the MRI findings in the patients were due to new myelin.

"These findings provide us with much greater confidence that going forward, a wide variety of myelin disorders might be candidates for therapy. Of course, each condition varies in terms of severity, how fast it progresses and the degree of brain injury it causes. This must all be taken into consideration as neurologists and stem cell biologist work to make further advances for these challenging brain disorders," Back said.

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Journal Reference:

1. Nalin Gupta, Roland G. Henry, Jonathan Strober, Sang-Mo Kang, Daniel A. Lim, Monica Bucci, Eduardo Caverzasi, Laura Gaetano, Maria Luisa Mandelli, Tamara Ryan, Rachel Perry, Jody Farrell, Rita J. Jeremy, Mary Ulman, Stephen L. Huhn, A. James Barkovich, and David H. Rowitch. Neural Stem Cell Engraftment and Myelination in the Human Brain. Sci Transl Med, 10 October 2012 4:155ra137 DOI: 10.1126/scitranslmed.3004373

 Researchers at Trinity College Dublin in collaboration with colleagues in the Department of Neurology at St Vincent's University Hospital and University College Dublin have recently reported new insights into cognitive changes in multiple sclerosis, using newly developed signal processing methods.

The findings have been recently published in the online journal PLOS ONE.

The multidisciplinary research involved neurologists, biomedical engineers and neuropsychologists. Their focus was on cognitive impairment which affects nearly 65% of multiple sclerosis (MS) patients and can occur in the absence of physical disability. Dysfunctions in speed of information processing, attention, memory and executive functions are most typically observed in MS patients, which have an adverse impact on daily life. It is important to recognise cognitive impairment as early as possible and to monitor its course frequently. However, neuropsychological tests to assess cognitive function can only be carried infrequently and do not provide an objective measure of cognitive impairment.

The research team was led by Professor Richard Reilly, Professor of Neural Engineering at Trinity College, and Professor Niall Tubridy, Department of Neurology at St Vincent's University Hospital. They addressed cognitive impairment assessment by developing new mathematical methods to extract information from MS subjects' scalp with electroencephalography (EEG) data that allows objective measurement of cognitive function at frequent intervals and more importantly offers new insights into the origins of this cognitive impairment in MS.

The team acquired EEG data using 128-scalp electrodes from 95 subjects (MS patients and controls subjects) while they completed a series of visual and auditory stimulus experiments. They then employed their newly developed mathematical methods to process the spatiotemporal EEG data developing a measure of cognitive function.

Professor Reilly commented that "objective, reliable EEG methods such as these developed in this study may have the potential to aid the detection and monitoring of cognitive impairment in MS, and therefore to complement clinical neuropsychological assessment."

Professor Tubridy added that "the relationship between pathological changes in the brain white and grey matter, neurophysiological and neuropsychological cognitive function is imprecisely defined in MS. This study provides new information on the impact of the cognitive impairments on the condition and will help us look for new interventions to improve the quality of life of our patients."

Professor Reilly added that "future studies will explore the neural information using new advanced data analysis methods such as approaches to model the distributed nature of EEG by incorporating activations and structural information from individual subjects' MRI image data." In addition, he said that "longitudinal studies of EEG scalp and deeper brain electrical activity spanning over several years are required to fully determine if EEG data has clinical utility in predicting the changes in cognitive function in MS."

— Researchers in Argentina report that women with multiple sclerosis (MS) who undergo assisted reproduction technology (ART) infertility treatment are at risk for increased disease activity. Study findings published in Annals of Neurology, a journal of the American Neurological Association and Child Neurology Society, suggest reproductive hormones contribute to regulation of immune responses in autoimmune diseases such as MS.

According to a 2006 report from the World Health Organization (WHO), MS affects 2.5 million individuals worldwide and is more common among women than men. While previous research found that up to 20% of couples in Western countries experience infertility, women with MS typically do not have diminished fertility except in those treated with cyclophosphamide or high-dose corticosteroids. Medical evidence shows sex hormones and those involved in ovulation (gonadotrophin-releasing hormone (GnRH)) play an important role in the development of autoimmune disorders.

"When MS and infertility coincide, patients seek ART to achieve pregnancy," explains Dr. Jorge Correale with the Raúl Carrea Institute for Neurological Research in Buenos Aires. "Given the role of some reproductive hormones in autoimmune diseases, those with MS receiving infertility treatments are at particular risk of exacerbating their disease."

To further understand the impact of infertility treatment on MS disease activity, researchers analyzed clinical, radiological, and immune response data in 16 MS patients who were subject to 26 ART cycles. The team recruited 15 healthy volunteers and 15 MS patients in remission not receiving ART to serve as controls.

Results show that 75% of MS patients experienced disease exacerbation following infertility treatment. MS relapses were reported in 58% of the cycles during the three month period following ART treatment. Furthermore, ART was associated with a seven-fold increase in risk of MS exacerbation and a nine-fold increase of greater MS disease activity on magnetic resonance imaging (MRI). The authors noted that 73% of exacerbations were new symptoms and 27% were attributed to a worsening of pre-existing symptoms.

Worsening was associated with three different mechanisms: 1) increase in the production of certain pro-inflammatory molecules known as cytokines (IL-8, IL-12, IFN-γ, and TGF-β by CD4+ T a GnRH-mediated effect); 2) increase in the production of antibodies against de myelin protein MOG, as well as B cell survival factor BAFF and antiapoptotic molecule Bcl-2 levels from purified B cells, these effects were a consequences of the rise of 17-β estradiol production induced by ART; and 3) authors demonstrated using an in vitro model of the blood-brain-barrier that ART facilitated the penetration of deleterious peripheral blood cells into the central nervous system, an effect mediated by the induction of the molecules IL-8, VEGF and CXCL-12.

"Our findings indicate a significant increase in MS disease activity following infertility treatment," concludes Dr. Correale. "Neurologists should be aware of possible disease exacerbation so they may discuss the benefits and risks of ART with MS patients."

A University of Adelaide researcher has published results that suggest a possible new mechanism to control multiple sclerosis (MS).

Dr Iain Comerford from the University's School of Molecular and Biomedical Science earned a three-year fellowship from MS Research Australia to work on this project. It is directed towards understanding how specific enzymes in cells of the immune system regulate immune cell activation and migration.

Along with his colleagues, Professor Shaun McColl and PhD students Wendel Litchfield and Ervin Kara, he focused on a molecule known as PI3Kgamma, which is involved in the activation and movement of white blood cells.

"There's already been worldwide interest in PI3Kgamma in relation to other human inflammatory disorders, such as diabetes and rheumatoid arthritis, and our study links this molecule and MS," said Dr Comerford, who is a Multiple Sclerosis Research Australia Fellow at the University of Adelaide.

Dr Comerford and his colleagues have now shown that this molecule is crucial for the development of experimental autoimmune encephalitis (EAE) in an animal model developed as a standard laboratory system for studying MS.

The team showed that a genetic alteration, which knocked out that particular molecule, resulted in a high resistance to the development of EAE and therefore protected against the nervous system damage typical of multiple sclerosis.

When the molecule is present, severe damage to the insulating myelin in the central nervous system was evident, resulting in inflammation in the spinal cord and myelin loss.

Following up on this result, the team then used an orally active drug that blocks the activity of the molecule PI3Kgamma at the first signs of disease onset. The drug even suppressed the development of EAE and reversed clinical signs of the disease.

"Our results so far have been very promising," Dr Comerford said.

"We've shown that by blocking PI3Kgamma, we can reduce the activation of self-reactive immune cells, reduce the release of inflammation-inducing molecules from immune cells, and also result in a dramatic reduction in the movement of immune cells into the central nervous system.

"Our hope is that future therapies for MS might target this molecule, which could very specifically dampen the damaging inflammation in the central nervous system.

"It will now be crucial to determine whether targeting these molecules could be a safe and effective way to treat MS in humans," Dr Comerford said.

Mr Jeremy Wright, CEO of MS Research Australia, said: "It is very rewarding to see that MSRA has been able to support these exciting developments by a young up-and-coming researcher. We will await his further results with great interest."

There are approximately 400,000 people in the United States with multiple sclerosis. Worldwide, the number jumps to more than 2.1 million people. Rather than a one-size-fits-all approach to treating the millions with multiple sclerosis, what if doctors could categorize patients to create more personalized treatments? A new study by researchers at Brigham and Women's Hospital (BWH) may one day make this idea a reality in the fight against the debilitating autoimmune disease.

A research team led by Philip De Jager, MD, PhD, BWH Department of Neurology, senior study author, has found a way to distinguish patients with multiple sclerosis into two meaningful subsets. The ability to categorize patients with multiple sclerosis may open new doors for treatment development.

The study will be electronically published on September 26, 2012 in Science Translational Medicine.

"Our results suggest that we can divide the multiple sclerosis patient population into groups that have different levels of disease activity," said De Jager. "These results motivate us to improve these distinctions with further research so that we may reach our goal of identifying the best treatment for each individual who has multiple sclerosis."

De Jager and his team extracted RNA — key molecules involved in making proteins from the instructions found in the DNA sequence — from blood cells of patients with multiple sclerosis. After analyzing the samples, they found distinct sets of RNA molecules among the patient samples. These unique sets formed a transcriptional signature that distinguished two sets of multiple sclerosis patients — MSa patients and MSb patients — with those in the MSa group having a higher risk for future multiple sclerosis relapse.

According to the researchers, knowing the category a person with multiple sclerosis is in may help doctors make more informed treatment decisions. For instance, since a patient who falls into the MSa category is more likely to experience relapse, her doctor may consider a stronger treatment for the patient.

In light of the discovery, the researchers remain cautious about the findings.

"Our study is an important step towards the goal of personalized medicine in MS, but much work remains to be done to understand under which circumstance and in combination with which other information this transcriptional signature may become useful in a clinical setting," said De Jager.

However, from the pre-clinical perspective, the researchers recognize that the findings are essential because they build on earlier studies that had suggested that this structure might be present.

"The study will further enable the community of MS researchers to build upon this transcriptional signature with other data in order to enhance patient care in the future," said De Jager.

 In multiple sclerosis, the immune system attacks nerves in the brain and spinal cord, causing movement problems, muscle weakness and loss of vision. Immune cells called dendritic cells, which were previously thought to contribute to the onset and development of multiple sclerosis, actually protect against the disease in a mouse model, according to a study published by Cell Press in the August issue of the journal Immunity. These new insights change our fundamental understanding of the origins of multiple sclerosis and could lead to the development of more effective treatments for the disease.

"By transfusing dendritic cells into the blood, it may be possible to reduce autoimmunity," says senior study author Ari Waisman of University Medical Center of Johannes Gutenberg University Mainz. "Beyond multiple sclerosis, I can easily imagine that this approach could be applied to other autoimmune diseases, such as inflammatory bowel disease and psoriasis."

In an animal model of multiple sclerosis known as experimental autoimmune encephalomyelitis (EAE), immune cells called T cells trigger the disease after being activated by other immune cells called antigen-presenting cells (APCs). Dendritic cells are APCs capable of activating T cells, but it was not known whether dendritic cells are the APCs that induce EAE.

In the new study, Waisman and his team used genetic methods to deplete dendritic cells in mice. Unexpectedly, these mice were still susceptible to EAE and developed worse autoimmune responses and disease clinical scores, suggesting that dendritic cells are not required to induce EAE and other APCs stimulate T cells to trigger the disease. The researchers also found that dendritic cells reduce the responsiveness of T cells and lower susceptibility to EAE by increasing the expression of PD-1 receptors on T cells.

"Removing dendritic cells tips the balance toward T cell-mediated autoimmunity," says study author Nir Yogev of University Medical Center of Johannes Gutenberg University Mainz. "Our findings suggest that dendritic cells keep immunity under check, so transferring dendritic cells to patients with multiple sclerosis could cure defects in T cells and serve as an effective intervention for the disease."

Many people with multiple sclerosis for years have taken the natural supplement Gingko biloba, believing it helps them with cognitive problems associated with the disease.

But the science now says otherwise. A new study published in the journal Neurology says Gingko biloba does not improve cognitive performance in people with multiple sclerosis. The research was published in the Sept. 5, 2012, issue of Neurology, the medical journal of the American Academy of Neurology. The current study was a more extensive look at the question after a smaller 2005 pilot study suggested there might have been some cognitive benefits in MS patients using the supplement. That study found that Gingko seemed to improve attention in MS patients with cognitive impairment.

But the larger follow-up study, conducted with patients at the Portland and Seattle Veterans Affairs medical centers, found no cognitive benefits to using Gingko.

"It's important for scientists to continue to analyze what might help people with cognitive issues relating to their MS," said Jesus Lovera, M.D., the study's lead author, a former fellow at the Portland VA Medical Center and former instructor in Oregon Health & Science University's Department of Neurology, where he did much of the work on the study. Lovera is now with the Department of Neurology at the Louisiana State University Health Sciences Center.

"We wanted to follow up on the earlier findings that suggested there may be some benefit. But we believe this larger study settles the question: Gingko simply doesn't improve cognitive performance with MS patients," said Lovera.

About one-half of people with MS will develop cognitive problems, and those cognitive problems can be debilitating in some people, said Dennis Bourdette, M.D., a co-author of the study, co-director of the VA MS Center of Excellence-West at the Portland VA Medical Center and chairman of the OHSU Department of Neurology. The most common problems relate to memory, attention and concentration, and information processing.

There is no known treatment that can improve cognition with MS patients — which is partly why MS patients and researchers had hoped that Gingko biloba could help.

Lovera was also the lead author in the 2005 study, conducted at OHSU. That study included 39 participants who were given Gingko biloba or a placebo. The new study included 120 participants given Gingko or a placebo.

The study was supported by a grant from the U.S. Department of Veterans Affairs Rehabilitation Research and Development Service.

Researchers from Brigham and Women's Hospital (BWH) are the first to discover that changes in monocytes (a type of white blood cell) are a biomarker for amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease. This finding also brings the medical community a step closer toward a new treatment for the debilitating neurological disease that affects approximately 30,000 Americans.

Cannabis-based medications have been demonstrated to relieve pain. Cannabis medications can be used in patients whose symptoms are not adequately alleviated by conventional treatment. The indications are muscle spasms, nausea and vomiting as a result of chemotherapy, loss of appetite in HIV/Aids, and neuropathic pain.