research

Early-life use of antibiotics disrupts gut microbiota in a rat model of multiple sclerosis (MS) and provokes nervous system autoimmunity, ultimately aggravating disease severity, new research shows. Results also indicate early-life antibiotic use may have unfavorable consequences on regulation of the immune system. The research article, “…

Almost one in five patients diagnosed with multiple sclerosis (MS) and referred to one of two MS-specialized centers in the U.S. were found to not have the disease, a study at those two centers reported. Migraine was the most common correct diagnosis eventually given these people. The retrospective study…

A protein called MMP-9 could be a predictive marker of progressive multifocal leukoencephalopathy development in patients with relapsing-remitting multiple sclerosis (RRMS) who are being treated with Tysabri (natalizumab), a study suggests. The study, “Dynamic changes of MMP-9 plasma levels correlate with JCV reactivation and immune activation in natalizumab-treated multiple sclerosis patients,” was published in the journal Nature Scientific Reports. Brain inflammation in multiple sclerosis patients occurs when immune cells breach the blood-brain barrier. This layer of cells protect the brain and its supporting fluids, such as cerebral spinal fluid (CSF), from dangerous agents circulating in blood. How easily immune cells can break through the blood-brain barrier depends on its porousness. For instance, it is known that decreasing the activity of matrix metalloproteinases (MMP) increases the protective layer’s permeability. Matrix metalloproteinases are a family of proteins responsible for the degradation of collagen and other proteins in the extracellular matrix, which provides structural and biochemical support to surrounding cells. One metalloproteinase, called MMP-9, has been extensively studied in multiple sclerosis. MMP-9 levels are elevated in the CSF of multiple sclerosis patients and considered a potential biomarker of disease activity and possible therapeutic target. Tysabri (marketed by Biogen) is one of the most effective treatments for RRMS currently available. It works by blocking the entry of immune cells into the brain. Tysabri is known to decrease MMP-9 levels in the CSF and serum in RRMS patients. However, Tysabri has been associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML). This rare and often fatal viral disease, caused by the John Cunningham virus (JCV), is characterized by progressive damage and/or inflammation at multiple sites in the brain. The reduced migration of immune cells across the blood-brain barrier induced by Tysabri is thought to be the cause of this increased PML risk. Whether MMP-9 is involved in this process has not been studied. To look at this, a team led by researchers from Sapienza University and Aldo Moro University in Italy investigated MMP plasma levels following Tysabri treatment in the context of JCV. The team specifically looked at how levels of MMP-9 were linked to disease-related processes. Samples from 34 RRMS patients being treated with Tysabri (intravenous dose of 300 mg every four weeks) were analyzed. As expected, results showed that MMP-9 plasma levels stabilized within one year of Tysabri treatment (up to 12 Tysabri infusions), although they began to steadily rise afterward (between 12 and 24 infusions). These increased MMP-9 plasma levels were not associated with clinical relapses in RRMS patients. "MMP-9 levels increased in plasma accordingly with [Tysabri] infusion number," the researchers wrote. In comparing JCV-positive and JCV-negative samples, the researchers observed an increase in MMP-9 plasma levels in JCV-positive samples. This result suggested that JCV circulation in peripheral blood could be implicated in the increase of MMP-9 levels. Interestingly, increased MMP-9 plasma levels were found to be correlated with immune cell activation. "Our findings suggest a potential pathogenic role of MMP-9 in the development of progressive multifocal leukoencephalopathy during [Tysabri] treatment, and its possible use as a marker of JCV reactivation,” the researchers wrote. Future studies are nonetheless needed to confirm these findings in larger groups of RRMS patients.

Treatment with PathMaker Neurosystems’ anodal trans‐spinal direct current stimulation (tsDCS), a non-invasive direct nerve stimulation tool called MyoRegulator, was found to effectively ease spasticity in mice with spinal cord injury, a study reports. A link between the ability to control muscle contraction and the levels of a specific neuronal…

Issues with social cognition can occur in relapsing-remitting multiple sclerosis (RRMS) patients even without the presence of cognitive impairment, and are related to damage in a specific brain region known as the amygdala, a study reports. The study, “Social cognition deficits and the role of…

Restrictive access policies by Medicare and a rising cost-sharing burden lead to an increased price of disease-modifying therapies for multiple sclerosis patients, according to new research. The findings also revealed that Medicare beneficiaries without a low-income subsidy may spend on average $6,894 for their MS treatments in 2019, with generic versions of Copaxone representing the highest burden. Approximately 25-30% of patients with MS are covered by Medicare through disability. In 2013, MS Medicare beneficiaries with MS and without low-income subsidies averaged $4,389 a year in out-of-pocket expenses, second only to hepatitis. Despite a greater number and diversity of DMTs for MS treatment, their price has increased substantially over the past two decades. In fact, expenses related to DMTs for MS are among the highest by class in the Medicare market. “It’s a dysfunctional market that lacks the typical incentives for most other consumer prices,” Daniel Hartung, the study’s lead author, said in an Oregon Health & Science University (OHSU) press release written by Erik Robinson. “Aside from the public optics, there are few incentives for companies not to raise prices. Most intermediaries in the drug distribution channel, including drug companies, benefit from higher prices,” Hartung said. These high prices may lead to reduced access, as insurance companies can restrict coverage or manage use through prior authorization or step-therapy policies, and high deductibles or cost-sharing components in health plans that increase the financial burden for patients. Now, a team at OHSU and the Oregon State University College of Pharmacy used prescription drug plan formulary files to analyze changes in coverage policies from 2007 to 2016, and to estimate out-of-pocket spending for DMTs for MS within Medicare Part D program, through which outpatient prescriptions are financed. Eleven DMTs available during the study period were analyzed. Tysabri and Lemtrada were not part of the analysis because they are delivered via intravenous infusion in the clinic setting, and are typically covered through Medicare Part B. Results revealed that the price for Betaseron , Copaxone 20 mg , Rebif, and Avonex — the four therapies available in 2007 — quadrupled over the 10-year study period. Except for Copaxone 40 mg and its 20 mg generic formulation (Glatopa, by Sandoz), prices for the other DMTs introduced after 2007 increased by 9–13% per year. These include Novartis’ Extavia (interferon beta-1b) and Gilenya (fingolimod), Biogen’s Plegridy (peginterferon beta-1a) and Tecfidera (dimethyl fumarate), and Sanofi Genzyme’s Aubagio (teriflunomide). In 2007, 99-100% of plans covered the four available medications, with the exceptions being Rebif (88%). These percentages fell to 54-89% in 2016. Coverage of the other DMTs varied between 21% (Extavia) to 92% for Copaxone 40 mg. In turn, coverage for the three oral options — Gilenya, Aubagio and Tecfidera — generally increased or was maintained over time, ranging from 46% for Aubagio to 83% for Gilenya. The use of prior authorization increased from 61-66% in 2007, to 84-90% in 2016. Also, the share of plans with at least one DMT available without limitations declined from 39% to 17%. The average projected out-of-pocket spending for 2019 across DMTs was $6,894. The highest projected out-of-pocket expenses ($8,219) are associated with generic glatiramer acetate, both Glatopa and Mylan’s 20 mg/mL and 40 mg/mL generic formulations, approved by the U.S. Food and Drug Administration in 2017. This is more than with any of Copaxone’s formulations. According to the team, this is the result of a higher coinsurance payment (37% vs. 25%) expected for generic medications compared to brand-name options, as well as the fact that manufacturers of generics do not provide discounts toward a beneficiary’s total out-of-pocket spending, unlike what is mandated by the Affordable Care Act for brand-name therapies. “This is a pernicious effect of the release of a generic and an unfortunate effect of Medicare rules,” Dennis Bourdette, MD, one of the study’s co-authors, said. A proposal by U.S. President Donald Trump's administration addresses this by eliminating manufacturer discounts from the calculation to determine a patient’s total out-of-pocket spending. Such strategy would reduce the disparity between brand-name and generic therapies, the researchers said. “In this study we found that Medicare beneficiaries with MS who require a [DMT] face considerable policy-related access restrictions and high out-of-pocket spending,” the researchers wrote. “There is an urgent need for policies that slow the growth of drug prices, improve access, and shield patients from excessively high out-of-pocket spending,” they concluded.

Previously unknown immune cell subtypes are present in the inflamed brain of mice models of multiple sclerosis (MS), a new study reports. According to the researchers, these subsets of myeloid cells (cells derived from hematopoietic stem cells in the bone marrow) can offer a strong basis for therapeutic targets in neuroinflammatory and…

The RhoE protein has been identified as being important for axons’  myelination and extension in the central nervous system, two processes that go awry in diseases like multiple sclerosis (MS). The findings stem from Pilar Madrigal’s doctoral thesis, “Role of the small GTPase RhoE in myelination and axonal tracts development.”…

Genetic variants that enhance the activity of the NLRP3 inflammasome or the interleukin-1 beta cytokine are linked to higher severity and progression of multiple sclerosis, a study suggests. Previous studies with mouse models of MS have shown that a complex of innate immune system receptors and sensors, known as the inflammasome, is likely a player promoting the immune system’s attack on the central nervous system in MS and, consequently, the loss of myelin. Follow-up studies showed that people carrying mutations that enhance the function of the NLRP3 inflammasome — one of the three components of the inflammasome complex — had a worse prognosis, once again supporting the role of the inflammasome in MS. Once activated, the inflammasome triggers an enzyme called caspase-1 that promotes the production of two very powerful proinflammatory cytokines called interleukin (IL)-1 beta and IL-18. To further evaluate the role of the inflammasome in MS, a team led by researchers at the Universidade de Sao Paulo in Brazil analyzed the genetic sequence of five inflammasome genes — NLRP1, NLRP3, NLRC4, IL-1 beta, and IL-18 — in blood samples retrieved from 264 patients diagnosed with MS or other demyelinating diseases. They also analyzed 233 healthy individuals used as controls. The team specifically looked at eight variations in certain nucleotides (the building blocks of DNA), called single nucleotide polymorphisms (SNPs). Previous studies reported a link between SNPs in inflammasome-related genes and certain forms of MS. Results showed that SNPs associated with low serum levels of IL-18 were significantly less frequent in MS patients than in controls. In contrast, variants that enhance the function of NLRP3 and IL-1 beta were associated with severity and progression of MS, as measured by the Expanded Disability Status Scale. These results suggest that the "activation of NLRP3 inflammasome could represent a risk factor for MS clinical presentation,” the researchers wrote. A particular variant in the NLRC4 gene was less frequent in patients whose disease progressed rapidly compared with those who had a slower disease, an intriguing observation, according to researchers, suggestive of a “protection effect of this variant against a bad prognosis.” Carriers of this variant also responded better to treatment with interferon-beta. Regarding MS type, the genetic variant that promotes the function of the IL-1 beta gene was significantly more frequent in progressive forms of MS than in relapsing-remitting MS, strengthening once again the negative effects of IL-1 beta in the disease. An analysis of inflammasome activity in blood monocytes, a group of immune cells, showed that the inflammasome is permanently activated in MS compared with healthy controls. "This study emphasizes that a constitutive activation of NLRP3 inflammasome, principally through IL-1 beta production, represents a risk factor for both the development of MS and the progression to severe forms of the disease. On the other hand, low IL-18 production and/or NLRC4 activation were beneficial for MS patients,” the team concluded.

People with multiple sclerosis may be twice as likely to develop deep-vein blood clots, a condition known as venous thromboembolism, than healthy people do, a study reports. But data linking the two is limited, and its researchers say further work is needed to understand if MS is directly related to…

MS Patients Sought to Test Alternative Chronic Pain Treatment Methods Do you have serious pain issues along with your MS? If so, you might be interested in this study that’s looking for participants. By the way, who says that pain isn’t an MS symptom? A clinical trial…

Reducing body temperature during physical exercise can help rewire the brain and improve motor control in patients with multiple sclerosis (MS), a new research study at Canada’s Memorial University shows. Physical exercise can have several benefits for patients with MS, including improved strength and reduced symptoms of fatigue and…

Editor’s note: “Need to Know” is a series inspired by common forum questions and comments from readers. Have a comment or question about MS? Visit our forum. This week’s question is inspired by the forum topic “Have you tried the high dose biotin protocol?“, from…

Anxiety and depression are associated with lower cognitive abilities in patients with multiple sclerosis (MS) other and immune-mediated inflammatory diseases such as inflammatory bowel disease (IBD) and rheumatoid arthritis, a study shows. These findings indicate the importance of managing symptoms of anxiety and depression in MS, as…

Stem cells tweaked in the laboratory have allowed researchers, reportedly for a first time, to generate and maintain ball-shaped cultures — called spheroids — of human brain cells in 3D that contain oligodendrocytes, the cells that produce myelin, along with neurons and the astrocytes that are essential to nerve cell health.

The question of how quickly to start a disease-modifying therapy (DMT) after a multiple sclerosis (MS) diagnosis is one that I frequently see when I browse online. It goes hand in hand with questions about which DMT is best to start with. There are many things to consider when…

Australian researchers from the University of Newcastle and the Hunter Medical Research Institute (HMRI) have received funding for two projects that will study unexplored areas in multiple sclerosis (MS). The projects, investigating the role of epigenetic differences in MS severity and treatment against MS-derived fatigue, received $211,000 AUD (about $151,300…

Herbicide Called Linuron Seen to Trigger Inflammatory Signals Linked to MS in Study This is only a mouse study, but this herbicide has been banned in Europe because of health concerns. Its effects seem worthy of further investigation. The herbicide linuron, commonly used with other herbicides, insecticides,…

The progressive decline in brain volume in multiple sclerosis (MS) patients, despite treatment with the disease-modifying therapy Tysabri (natalizumab), is driven by atrophy — shrinkage due to the degeneration of cells — in gray matter and not white matter structures, a new study reports. This finding points to new markers…

Subpopulations of oligodendrocytes — cells that produce the myelin sheath that protects nerve fibers — are altered in patients with multiple sclerosis, a study shows. These findings suggest that oligodendrocyte diversity and the different functions of these subpopulations might have a greater role in the disease than previously thought. The severity of MS varies greatly, and the patient's disability level does not correlate well with the degree of myelin loss. This suggests that other factors contribute to MS severity. One such factor may be that oligodendrocytes are heterogeneous — diverse in makeup and function. For example, oligodendrocytes in mouse spinal cords are known to naturally produce longer myelin sheaths than oligodendrocytes in the mouse brain. Additionally, individual oligodendrocytes have been shown to have different molecular makeups. However, the extent of human oligodendrocyte diversity and its possible contribution to MS pathology remains unknown. Researchers from the Karolinska Institutet and the MRC Centre for Regenerative Medicine studied the differences of individual human oligodendrocytes from healthy and MS brains to assess their diversity. Specifically, the team examined oligodendrocytes from the white matter areas of post-mortem human brains both from MS and non-MS patients. The team examined the RNA content — the messenger molecule carrying instructions from DNA for the production of proteins — from individual oligodendrocytes. Researchers identified groups of RNA molecules that defined features of oligodendrocytes from healthy human white matter. Some of these groups match those that defined oligodendrocytes in healthy mice. Strikingly, some of these RNA molecules in healthy brains were under-represented in oligodendrocytes from MS brains, whereas others were more prevalent. “We found that oligodendrocytes are a diverse population of cells and that different types are likely to have different functions in the brain,” Charles ffrench-Constant, the study's co-lead author, said in a Karolinska Institutet news release written by Katarina Sternudd. These differences in oligodendrocyte RNA content may indicate different functional states of oligodendrocytes in MS lesions. “The proportions of different resident oligodendrocytes in the lesions are changed, along with their properties, suggesting that they might have important roles in MS,” said Eneritz Agirre, PhD, a study co-author. Furthermore, the researchers believe that this altered diversity in oligodendrocytes in MS may be important to understand disease progression and develop therapeutic approaches. “Understanding which types of oligodendrocytes are most beneficial in repairing myelin will be crucial for maximizing the chances of developing much-needed treatments for MS,” said Anna Williams, PhD, study co-lead author. The team concluded that the changes in different oligodendrocyte subpopulations in MS suggest "a more complex role of these cells in the pathology of the disease, but also in regeneration of new cells,” said Gonçalo Castelo-Branco, PhD, another study co-lead author.

Tiny ruptures in the cell membrane of nerve fibers enable the entry of calcium and ultimately lead to their degeneration, a study in a mouse model of multiple sclerosis (MS) suggests. The study, “Calcium Influx through Plasma-Membrane Nanoruptures Drives Axon Degeneration in a Model of Multiple…

A protein marker for activated immune cells called Chi3I3 is key for the production of myelin-forming cells, and may become a target to boost myelin repair in multiple sclerosis (MS), according to a new study. The research, “Chi3l3 induces oligodendrogenesis in an experimental model of autoimmune…

Editor’s note: “Need to Know” is a series inspired by common forum questions and comments from readers. Have a comment or question about multiple sclerosis? Visit our forum. This week’s question is inspired by the forum topic “Can there be a connection between Epstein-Barr virus…

Endothelial cells, those lining the inside of small blood vessels, promote clearance of myelin debris — a common detrimental outcome of demyelinating diseases such as multiple sclerosis (MS) or spinal cord injury. However, in its path to clear the brain from myelin debris, endothelial cells trigger more damaging mechanisms, promoting…

Novartis and the University of Oxford’s Big Data Institute (BDI) have established an alliance to advance the use of medical data for spotting disease patterns and assessing patients’ responses to treatment. The initiative seeks to enable more informed clinical decision-making and improve the development of treatments for complex diseases.

Treatment with Ocrevus (ocrelizumab) has superior or comparable effectiveness and a similar safety profile to other available disease-modifying treatments (DMTs) for treating relapsing multiple sclerosis (MS), according to a new review study. The research, “Systematic review and network meta-analysis comparing ocrelizumab with other treatments for…

The herbicide linuron, commonly used with other herbicides, insecticides and fungicides to control the growth of grass and weeds, may be an important environmental risk factor in the development of neurological diseases that include multiple sclerosis, researchers suggest. Used in the U.S. and other countries — but recently…

A small molecule called Sephin1 may be able to significantly delay harm to neurons in multiple sclerosis (MS) by protecting oligodendrocytes, limiting the autoimmune response, a mouse study reports. The study, “Sephin1, which prolongs the integrated stress response, is a promising therapeutic for multiple sclerosis,” was published in the journal Brain. MS is thought to be caused by immune-mediated inflammation that damages the myelin — an insulating sheath around nerve cells. For this reason, current MS disease-modifying treatments focus on immune-mediated inflammation. Although these treatments moderate disease relapses, their impact on disease progression is unclear. Previous studies have demonstrated that oligodendrocytes — cells that produce myelin — are critical in protecting against neuron demyelination and axon (nerve fiber) damage. As a result, researchers have been keen to develop alternative therapeutic approaches that protect oligodendrocytes, and ultimately limit disease progression.  A signaling pathway called integrated stress response that acts as a natural defense system to protect cells has been shown to reduce the inflammatory impact on oligodendrocytes. This response is triggered by phosphorylation (a chemical reaction) of a protein called eukaryotic initiation factor 2 alpha (eIF2α), and reduces the total production of proteins, instead promoting the synthesis of protective proteins in the cells. Conversely, the integrated stress response can be cut off by dephosphorylation of eIF2α. Sephin1 was shown to inhibit the dephosphorylation of eIF2α, prolonging the protective response. In this study, researchers at the University of Chicago proposed that Sephin1, by producing this response, could protect oligodendrocytes and slow the progress of the disease. The team tested their hypothesis in a mouse model called experimental autoimmune encephalomyelitis (EAE), which is similar to MS in humans. Results showed that treatment with Sephin1 did inhibit eIF2α dephosphorylation in EAE mice, triggering a protective response against inflammation. More importantly, myelin-producing oligodendrocytes were also protected, and disease onset was significantly delayed. This correlated with diminished oligodendrocyte loss, protected neuronal axons and myelin, and prolonged integrated stress response. In addition, Sephin1 decreased the levels of inflammatory immune T-cells, and the production of inflammatory signals within the central nervous system. "By protecting oligodendrocytes and diminishing demyelination, we also reduce the generation of myelin debris,"  Brian Popko, PhD, the study's senior author, said in a press release. "The decreased exposure to myelin fragments should also limit the auto-immune response." Popko is the Jack Miller professor of neurological disorders, and director of the Center for Peripheral Neuropathy at the University of Chicago. The effects of Sephin1 were also combined with interferon-beta treatment — an anti-inflammatory first-line MS therapy. Researchers found that the combination was more effective than the therapies given separately. "Encouragingly, adding Sephin1 to the established anti-inflammatory MS drug interferon beta provided additive benefits to the mouse MS model," said study co-author Yanan Chen, PhD, a postdoctoral fellow in the Popko laboratory. The team concluded that the results "suggest that a neuroprotective treatment based on the enhancement of the integrated stress response would likely have significant therapeutic value for multiple sclerosis patients." Treatment with Sephin1, they say, "could lead to a better clinical outcome in multiple sclerosis patients as a safe neuroprotective drug, perhaps when used in combination with immune-modulatory therapies." Sephin1 has been patented and licensed to InFlectis BioScience, a French biotech company.

Relapsing-remitting multiple sclerosis (RRMS) patients on Gilenya (fingolimod) have fewer relapses and stay on treatment longer than those taking Tecfidera (dimethyl fumarate) or Aubagio (teriflunomide), according to a new study. The research, “Comparison of fingolimod, dimethyl fumarate and teriflunomide for multiple sclerosis,” was published…

Katerina Akassoglou, PhD, a leading neurology researcher at the Gladstone Institutes at the University of California, San Francisco (UCSF), won the 2018 Barancik Prize for Innovation in Multiple Sclerosis Research. Akassoglou will receive the award and deliver the Prize lecture at the Americas Committee for Treatment…