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Archive for the tag “Neurology”

Researchers Find That Immune B Cells from People with MS May Harm Nerve Cells

SUMMARY:

  • Researchers co-funded by the National MS Society have found that immune B cells obtained from the blood of people with relapsing-remitting MS secrete products that can be toxic to nerve cells grown in lab dishes.
  • This study offers new insight into how B cells may contribute to nervous system damage in MS.
  • The team is now conducting further studies to identify the toxic factor or factors secreted by the B cells, and when and how they may act in people with MS, and to answer questions such as whether they are unique to MS, whether they are also evident in people with progressive MS.
  • Drs Robert P Lisak, Joyce Benjamins (Wayne State University), Amit Bar-Or (McGill University and currently at University of Pennsylvania) and colleagues published their findings in the Journal of Neuroimmunology (2017 Aug 15;309:88-99, published online May 17)

DETAILS
Background: While scientists still don’t know what causes multiple sclerosis, they do know that immune-system attacks are involved, resulting in damage to the myelin that insulates nerve fibers and to nerve cells and fibers themselves. Immune T cells have typically been named as culprits, but it has become clear that immune B cells, another type of white blood cell, are also involved in MS. Research and studies on B cells, including early studies supported by the National MS Society, eventually led to successful clinical trials and approval of Ocrevus™ (ocrelizumab – Genentech, a member of the Roche Group) to treat people with primary progressive and relapsing-remitting MS. Ocrevus depletes certain B cells.

The Study: The current study builds on the researchers’ earlier findings that B cells from the blood of people with relapsing-remitting MS – but not blood from healthy individuals – are toxic to certain cells that build myelin. In this study, the team isolated B cells in the laboratory from the blood of 13 women and men with relapsing-remitting MS who were not receiving disease-modifying treatment or recent steroids, and 13 controls without MS.

The researchers found that products released by B cells from the people with MS were toxic to both rat and human nerve cells grown in lab dishes, while cells from the controls did not incur the same damage. The nerve cells died from apoptosis – a type of self-destruct program – and not, as might be expected, from cell disintegration, or from immunoglobulins (antibodies) that have been identified as culprits in the MS attack.

Drs Robert P Lisak, Joyce Benjamins (Wayne State University), Amit Bar-Or (McGill University and currently at University of Pennsylvania) and colleagues published their findings in the Journal of Neuroimmunology (2017 Aug 15;309:88-99, published online May 17). This study was supported by the National MS Society (USA), the Research Foundation of the MS Society of Canada, and others.

Next Steps: This study offers new insight into how B cells may contribute to nervous system damage in MS. The team is now conducting further studies to identify the toxic factor or factors secreted by the B cells, and when and how they may act in people with MS. They are using “proteomics” for this work, advanced technologies the can identify and quantify numerous molecules simultaneously, along with other approaches. They also plan to answer questions such as whether the toxic B cells are unique to MS or are found in other immune mediated disease, which subsets of B cells produce the toxic effects and whether they are also evident in people with progressive MS.

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Learn more about research on the immune system in MS

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Dawson’s Fingers ???

“Dawson’s fingers” is the name for the lesions around the ventricle-based brain veins of patients with multiple sclerosis. The condition is thought to be the result of inflammation or mechanical damage by blood pressure around long axis of medular veins.

Dawson’s fingers spread along, and from, large periventricular collecting veins, and are attributed to perivenular inflammation.

Lesions far away from these veins are known as Steiner’s splashes.

Sometimes experimental autoimmune encephalomyelitis has been triggered in humans by accident or medical mistake. The damage in these cases fulfils all the pathological diagnostic criteria of MS and can therefore be classified as MS in its own right. The lesions were classified as pattern II in the Lucchinetti system. This case of human EAE also showed Dawson fingers.

New MS Research

This month in Lancet Neurology, a Canadian research team reports there is a pre-clinical phase in MS. The study used health administration records from four Canadian provinces (British Columbia, Saskatchewan, Manitoba, and Nova Scotia). Due to the nature of the Canadian health-care system, these provinces have computerized health-care records on >99% of residents, including hospital discharges, physician billing, prescription on records, and dates of all medical visits – all records can be linked by a unique health-care number assigned to individuals. Using these records, medical histories for 14,428 MS cases and 72,059 controls were included for this study. They compared health-care utilization in the same five-year period prior MS diagnosis between cases and temporally matched controls.

Interestingly, five years before a MS diagnosis, the number of hospital admissions for people who eventually developed MS was 26% higher than controls, and this increased to 78% higher a year before MS diagnosis. A similar pattern was observed for physician billing (5 years before diagnosis: 24% higher in people with MS than controls; 1 year before diagnosis: 88% higher in people with MS than controls). There was also a substantial increase in the number of prescribed drug classes in people with MS compared to controls (5 years before diagnosis: 23% higher; 1 year before diagnosis: 49%  higher). These results clearly demonstrate a pre-clinical stage for MS where subtle symptoms exist before clinically definitive symptoms (also known as a prodromal stage). With further research, we can explore these subtle symptoms and hopefully diagnose MS earlier and initiate therapeutics earlier, slowing the rate of progression of MS.

From: When do MS symptoms start? By Farren Briggs PhD, ScM; The Accelerated Care Project for Multiple Sclerosis

Interesting Results…

Gene That Boosts Resistance to Malaria linked to Susceptibility to MS and Lupus in Sardinia

Researchers from Italy found a strong association between the gene that instructs the molecule “BAFF” and susceptibility to MS and lupus in studies of nearly 6,000 people in Sardinia. The BAFF gene is crucial to activation of immune B cells and is also associated with resistance to malaria. Malaria was common in Sardinia until it was eradicated in 1950. The rates of MS and certain immune-mediated diseases are high in Sardinia. Further research is necessary to confirm whether this high rate is related to BAFF, and whether MS could be treated by a therapy that targets BAFF.

Read more about this study from the Genetic Literacy Project

Read the scientific summary of the paper in The New England Journal of Medicine

Read more about efforts to end MS forever

 
 

Novel Protein Identified Inside Cells During MS Inflammation May Help Explain Nerve Damage

Researchers from the University of Alberta in Canada report that levels of Rab32 – a protein that directs traffic between cell organs – are increased in sites of active inflammation in brain tissue obtained from people with MS and in mouse models of MS-like disease. This increase was linked to the destruction of nerve cells. If the results are confirmed, this knowledge could explain part of the neurodegenerative process that leads to progression of disability in MS and could be a target for development of effective MS treatments.

Read more on ReliaWire
Read the open access paper in Journal of Neuroinflammation
Read more about Research to stop MS in its tracks

Australian Team Finds Possible Molecular Pathway for MS Progression

Researchers from Australia report that the amount of molecules in a sequence of chemical reactions called the kynurenine pathway differs between people with MS and healthy controls, and between people with relapsing-remitting and progressive forms of MS. The kynurenine pathway is activated by chronic inflammation, and its activation may be involved in nerve damage and MS progression.  The kynurenine pathway has also been implicated in other neurological and psychiatric disorders. The MS-specific findings, and the potential use of the kynurenine pathway in a diagnostic test, will need to be explored in additional studies.

This work was funded by the National Health and Medical Research Council and Multiple Sclerosis Research Australia. The researchers used several repositories to complete these experiments – the Accelerated Cure Project for MS, The Human Brain and Spinal Fluid Resource Center (which is sponsored by the National MS Society, among others), and the Tasmanian MS Longitudinal Study.

New Results Show that Magnetic Stimulation of Brain May Improve Working Memory and Brain Connectivity in People with MS

Summary

  • People with MS, but not healthy controls, showed improvements in working memory, brain activity, and “connectivity” (how parts of the brain interact with one another), after treatment with Repetitive Transcranial Magnet Stimulation (rTMS). This device generates electromagnet pulses that stimulate brain activity.
  • rTMS may have a future role in cognitive rehabilitation in people with MS, but further, larger studies are necessary to confirm the safety and effectiveness of this intervention and its long-term effects.
  • The team (Hanneke Hulst, MD, of VU Medical Center in Amsterdam, and others) has published results in Journal of Neurology, Neurosurgery, and Psychiatry (Published Online First: 14 December 2016).

Background: Repetitive Transcranial Magnet Stimulation (rTMS) was approved by the FDA as a treatment for major depression. A device that generates electromagnet pulses is placed on the scalp with the idea of stimulating specific brain activity. Studies have shown that people with MS who received rTMS showed significant decreases in depression. This team looked at whether rTMS improved working memory (short-term memory needed for tasks such as mental arithmetic), which can be affected in people with MS.

The Study: Investigators administered rTMS – or a “sham” version of lower intensity – to an area of the brain associated with working memory in17 people with MS and 11 healthy controls. None of the participants showed signs of impaired memory at the outset of the study. A potential adverse event of rTMS is seizures, so participants were excluded if they were taking medicine that put them at risk for seizures, or had MS brain lesions in particular areas. Before and after, participants underwent imaging and extensive neuropsychological testing aimed at investigating memory. They also completed a working memory task while undergoing functional MRI, which measures brain activity during tasks.

At the beginning of the study, there were no differences in working memory between people with MS and controls. After treatment, the results suggested improvements among people with MS in working memory, brain activity, and “connectivity” (how parts of the brain interact with one another). These changes were not seen in controls.

The team (Hanneke Hulst, MD, of VU Medical Center in Amsterdam, and others) has published results in Journal of Neurology, Neurosurgery, and Psychiatry

Next Steps: The authors comment that this small study implies that rTMS may play a future role in cognitive rehabilitation in people with MS. However, the study is limited by the small sample size and the fact that participants did not have obvious cognitive problems. Further studies that address these factors are necessary to confirm the safety and effectiveness of this intervention for people with MS and its long-term impact on day to day activities.

Read more about cognitive changes that affect people with MS

 

Positive Results Announced from Clinical Trial of BAF-312 (Siponimod) in Secondary Progressive MS

Summary

Results presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) provided additional details from a 60-month, phase III clinical trial of the experimental oral therapy siponimod (BAF312, Novartis Pharmaceuticals AG) involving 1,651 people with secondary progressive MS.

The trial met its primary endpoint of reducing the risk of disability progression compared with inactive placebo. Those on active treatment had a 21% reduced risk of disability progression compared to those on placebo. Secondary endpoints suggested that those on active therapy had 23.4% lower average change in brain volume and reduced lesion volume.

The therapy was generally well tolerated and similar to adverse events reported for similar compounds.

Details

Background: Siponimod (BAF312) is an experimental immune system-modulating therapy that was designed to be a more selective sphingosine 1-phosphate receptor modulator than Gilenya® (fingolimod, Novartis International AG). Gilenya, was approved in 2010 for adults with relapsing forms of MS to reduce the frequency of clinical relapses and to delay the accumulation of physical disability. Siponimod previously demonstrated safety and efficacy on MRI scans in a phase II study in people with relapsing-remitting MS (The Lancet Neurology, 2013 Aug;12(8):756-67).  Siponimod is thought to act by retaining certain white blood cells in the body’s lymph nodes, keeping them out of circulation and from entering the central nervous system. Siponimod also distributes effectively to the central nervous system (brain and spinal cord) where it may have direct anti-inflammatory or other effects.

The Study: Participants were randomly assigned to take siponimod or placebo capsules daily for up to 60 months. The primary endpoint of the study was reducing the risk of disability progression, as measured by the EDSS scale at three months. Secondary endpoints included reducing the risk of disability progression as measured by the EDSS at six months versus placebo, the risk of worsening mobility as measured by the timed 25-foot walk test, disease activity as observed on MRI scans, relapse rate, and safety/ tolerability.

Results:  Results were presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) on September 17, 2016. The trial met its primary endpoint of reducing the risk of disability progression compared with inactive placebo. Those on active treatment had a 21% reduced risk of disability progression (confirmed at 3 months) compared to those on placebo. Secondary endpoints suggested that those on active therapy had at 26% reduced risk of disability progression (confirmed at 6 months), a 23.4% lower average change in brain volume, and reduced MRI-detected brain lesion volume. There was no significant difference seen between groups in the timed 25-foot walk. Relapse rates were significantly lower in those taking siponimod.

Safety: The therapy was generally well tolerated and similar to adverse events reported for similar compounds. Serious adverse events occurred in 16.7% of participants. The serious adverse events reported to be more likely for those taking siponimod included nervous system disorders and infections.

Comment:
“These results suggest a modest benefit for people with secondary progressive MS, which is a positive step forward in the global effort to speed solutions for people living with this chronic form of the disease,” said Timothy Coetzee, PhD, Chief Advocacy, Services and Research Officer at the National MS Society. “We look forward to learning additional details about its potential benefit and safety.”

Study suggests antibody may have therapeutic effect on MS

Researchers have developed an antibody with potential therapeutic effects against multiple sclerosis. The discovery opens up a new strategy for controlling the disease.

For the cells of the immune system circulating in the bloodstream to reach the central nervous system, they must penetrate the blood-brain barrier and blood-spinal cord barrier. During previous work, the authors studied a factor involved in opening the blood-brain barrier, the NMDA receptor. They found that blocking the interaction of this receptor with tPA has beneficial effects linked with maintaining the integrity of the barrier.

Scientists at the Institut National de la Santé et de la Recherche Médicale, in France, developed a monoclonal antibody (Glunomab) directed against the specific site on the NMDA receptor to which tPA binds. In cellular models of the human blood-brain and blood-spinal cord barriers, the use of this antibody prevented opening of the barrier under inflammatory conditions, limiting the entry of lymphocytes. The team then tested the therapeutic effects of the antibody in an experimental mouse model of MS. After intravenous injection of Glunomab, the progression of partial or total paralysis of the limbs – as assessed by a clinical score – was blocked. In these treated mice, this effect was linked with reduced infiltration of lymphocytes into the nervous tissue, and reduced demyelination.

Results of mouse model studies sometimes do not translate to humans and may be years away from being a marketable treatment. However, the authors argue that by preventing myelin destruction by the cells of the immune system, this strategy might represent a promising therapy for the control of MS.

The study was published in the journal Brain.

Study Shows Expansion of Stem Cell Clinics in the U.S. and the Need for Better Oversight

Researchers have published a paper describing the proliferation of stem cell clinics in the United States and ethical issues and regulatory concerns that come with marketing unproven treatments for many conditions. Their study shows that many different types of unproven stem cell treatments are being offered, and highlights concerns for the safety of people who undergo these treatments.

There is exciting progress being made through innovative research related to the potential of many types of stem cells for slowing MS disease activity and for repairing damage to the nervous system. At present, there are no approved stem cell therapies for MS. People need the best available information to understand this exciting area of research and make decisions related to this complex issue.

The paper’s findings support the need for stem cell therapy to be explored in the context of carefully conducted clinical trials that can determine what the optimal cells, delivery methods, safety and actual effectiveness of cell therapies might be for people with MS.

Positive Results from Study of Bone Marrow-Derived Stem Cells in People with Aggressive, Relapsing MS

Summary

  • Researchers in Canada have published results of a long-term trial of an individuals’ own (autologous) hematopoietic (blood cell-producing) stem cell transplantation. The study involved 24 people with aggressive relapsing-remitting MS whose disease was not controlled with available therapies.
  • Three years after the procedure, 70% remained free of disease activity, with no relapses, no new MRI-detected inflammatory brain lesions, and no signs of progression.
  • None of the surviving participants, who were followed for 4 to 13 years after the procedure, experienced clinical relapses or required MS disease-modifying therapies to control their disease, and 40% experienced reductions in disability.
  • One of the participants died and another required intensive hospital care for liver complications. All participants developed fevers, which were frequently associated with infections, and other toxicities.
  • Additional research is focusing on figuring out who might benefit from this procedure and how to reduce its risks.

“These results suggest that aggressive MS may be stopped with an effective but risky procedure, for a subset of people,” said Dr. Bruce Bebo, Executive Vice President, Research, at the National MS Society. “Additional research by investigators around the world is focusing on figuring out who might benefit from this procedure and how to reduce its risks, which can include death.”

Details
Background: An experimental procedure that has been explored for several years in MS is called “autologous hematopoietic (blood cell-producing) stem cell transplantation” – or HSCT. This procedure has been used in attempts to “reboot” the immune system, which launches attacks on the brain and spinal cord in people with MS.

In HSCT, the stem cells (derived from a person’s own bone marrow or blood) are stored, and the rest of the individual’s immune cells are depleted by chemotherapy. Then the stored stem cells are reintroduced by infusion into the vein. The new stem cells migrate to the bone marrow and over time produce new blood cells, including immune cells. The goal of this currently experimental procedure is to establish a new immune system that no longer recognizes myelin and other nervous system tissue as dangerous. In theory, this should stop the attacks that lead to tissue damage and disability.

There are a number of laboratories around the world testing variations of HSCT for the treatment of autoimmune diseases, including MS. Preliminary findings suggest this is a promising, but potentially risky strategy for the treatment of MS.

The Study: Drs. Harold Atkins, Mark Freedman and team at the Ottawa Hospital, University of Ottawa and other institutions in Canada conducted a Phase 2 trial of HSCT that involved 24 people with aggressive relapsing-remitting MS whose disease was not controlled with available therapies. No control group was used which would have enabled comparison against the results found in the treatment group. The procedure used by this group included complete destruction of bone marrow cells and an additional step that enriched the transplanted cells for stem cells.

Results – Safety: One of the participants died of transplantation-related complications that caused liver failure and another required intensive hospital care for liver complications. The treatment regimen was modified over the course of the study to reduce toxicity, but all participants still developed fevers, which were frequently associated with infections.

Results – Effectiveness: Three years after the procedure, 70% of the participants remained free of disease activity, meaning they had no relapses, no new MRI-detected inflammatory brain lesions, and no signs of progression. The remaining 30% experienced progression of disability. In addition, for the entire follow-up period ranging from 4 to 13 years after the procedure, of the 23 survivors:

  • None experienced clinical relapse, had new active inflammatory MRI brain lesions, or required MS disease-modifying therapies to control their disease.
  • The average rate of brain atrophy (shrinkage), a measure that has been linked to MS progression, returned to levels associated with normal aging.
  • 40 percent experienced some lasting reversal of disability such as vision loss, muscle weakness and balance problems.
  • Some were able to return to work or school.

The results were published online on June 9, 2016 in The Lancet.  Major funding for the study came from the MS Society of Canada and its affiliated Multiple Sclerosis Scientific Research Foundation.

Next Steps: Rigorous clinical trials of stem cell therapies are needed to determine their safety and effectiveness in people with MS. Trials of this and other stem cell therapy approaches are taking place in Canada, the United States, Europe and elsewhere. To help explore the potential of stem cell therapy, in November 2015, the International Conference on Cell-Based Therapy for Multiple Sclerosis was convened in Lisbon, Portugal under the auspices of the International Advisory Committee on Clinical Trials in MS (a group jointly sponsored by the National MS Society and the European Committee for Treatment and Research in Multiple Sclerosis). Seventy leading researchers and clinicians conferred on clinical trials needed to provide answers about which types of cells, which route of delivery, and which types and stages of disease, would be the most promising approach for treating MS. Read more about this meeting

Read more about stem cells and MS

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