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MS News Archive July 2015

MSPrecise accuracy revealed (31/07/15)
A new study testing Amarantus Diagnostics’ MSPrecise on multiple sclerosis patients identified the test as a specific and sensitive diagnostic test for multiple sclerosis. The test accurately diagnosed 84 per cent of multiple sclerosis patients from a broad range of subjects with potential neurological diseases.

“MSPrecise scoring is a powerful approach to aid clinicians in this task,” said Colin Bier, Chief Development Officer of Amarantus Diagnostics, in information provided to Multiple Sclerosis News Today. “In this study there is an overall MSPrecise accuracy of 84 per cent in identifying relapsing-remitting multiple sclerosis (RRMS) patients or patients that will develop RRMS, which represents a huge benefit to physicians.”

The 2013 study, MSPrecise: A Molecular Diagnostic Test For Multiple Sclerosis Using Next Generation Sequencing, has now been published in the journal Gene. Initiating the study, researchers at UT Southwestern Medical Center, UMass Memorial Medical Center, John Hopkins University, and DioGenix Inc. were interested in testing the accuracy of MSPrecise. This test uses samples of cerebrospinal fluid to analyze mutations in the VH4 gene of B-cells. B-cells have been shown to accumulate VH4 gene mutations in patients with the early stages of RRMS. The number of specific replacement mutations can be quantified to “score” the patient for the likelihood of developing or converting to RRMS, giving clinicians another tool in their toolbox for diagnosing multiple sclerosis.

“Given the early misdiagnoses that often occur with multiple sclerosis, physicians have an increasing need for new methods to accurately diagnose their patients,” said Bier. In the study, the researchers obtained cerebrospinal fluid cell pellets from 26 patients with an undiagnosed neurological disease and 13 patients with confirmed RRMS. When the researchers used MSPrecise to amplify VH4 gene segments, they were able to predict RRMS with a sensitivity of 75 per cent and a specificity of 88 per cent in the undiagnosed patients and an accuracy of 84 per cent in the RRMS patients.

Amarantus is continuing to develop the ability to diagnose RRMS and has a blood-based version of MSPrecise in the works. The company also conducted a study that showed additional features for MSPrecise that increase the accuracy of the test. “In early 2015, Amarantus reported data from a later study that showed a significant increase in the accuracy of MSPrecise when adding oligoclonal banding (OCB) to the algorithm,” said Bier. “We intend to publish those data combining MSPrecise and OCB in the near future.”

In addition, Amarantus will continue to validate the current iteration of MSPrecise.

“Our immediate focus is to conduct a CLIA-validation study in order to make the test commercially available, and plans are being finalised in this regard,” said Gerald E. Commissiong, President & CEO of Amarantus Bioscience Holdings. “We also plan to conduct future investigational studies to determine whether MSPrecise scoring using NGS platforms may be utilised to identify clinically isolated syndrome (CIS) patients who will convert to RRMS. Additionally, a more expansive clinical study with a larger patient cohort including several sub-cohorts of RRMS patients on disease modifying therapies and OND patients is also planned.”

According to Amarantus, “MSPrecise would augment the current standard of care for the diagnosis of multiple sclerosis by providing a more accurate assessment of a patient’s immune response to a challenge within the central nervous system.” Amarantus also hopes to use NGS to discern between individuals who may develop progressive multiple sclerosis, increasing the population of patients the company helps.

Source: Multiple Sclerosis News Today © BioNews Services 2015 (31/07/15)

Study highlights altered cells in immune system of MS patients (31/07/15)
A new study, Polymorphonuclear Cell Functional Impairment In Relapsing Remitting Multiple Sclerosis Patients: Preliminary Data has shown how polymorphonuclear cells — important players of the innate immune system — are altered in multiple sclerosis patients.

The study was published in the journal PLOS One.

A key component of the innate immune system are polymorphonuclear cells (PMNs), which are responsible for phagocytosis (ingestion or engulfment other cells or particles) and production of reactive oxygen species (ROS), key steps in combating infections. Notably, MS patients were reported to exhibit decreased levels of PMNs with altered functions, which may cause the increase in infection risk.

In this new research, the authors investigated how the functional capacities of PMNs are altered in relapsing remitting multiple sclerosis (RRMS), characterized by clearly defined attacks of worsening neurologic function which are then followed by periods of partial or complete recovery periods (called remissions) when compared to PMNs from healthy individuals. Specifically, they measured the ability of PMNs retrieved from MS patients to secrete cytokines, produce ROS, and regulate cell death when infected with a bacteria, Klebsiella pneumonia and a fungus, Candida albicans.

The team found that while PMNs from healthy control individuals and untreated RRMS patients exhibit a similar intracellular killing activity against both Klebsiella pneumoniae and Candida albicans, PMNs from RRMS patients that received MS treatment (drugs that modulate or suppress the activity of the immune system) had a significant decrease in their ability to actively kill the intracellular organisms. To determine if indeed the treatment was the underlying cause of the decline in PMNs killing activity, the researchers pre-treated healthy patients’ PMNs with an immunosuppressive drug. They observed that the drug-pretreated healthy subjects’ PMNs also had reduced killing activity — significantly lower then the activity observed without the pre-treatment.

No other alterations, production of reactive oxygen species and cell death regulation were observed between the different subjects analysed, which included healthy controls as well as untreated and treated RRMS patients.

Therefore, although the team recognises some limitations to their study, they suggest that the higher incidence of microbial infections in treated RRMS patients is due to an impairment of PMN activity. Additionally, studies are mandatory to further understand the link between MS, the innate immune system and therapy so that patients can be managed and receive the appropriated treatments according to their risk of infection.

Source: Multiple Sclerosis News Today © BioNews Services 2015 (31/07/15)

‘Building confidence improves quality of life’ (27/07/15)
Researchers from Case Western Reserve University's Frances Payne Bolton School of Nursing have been studying what makes MS patients happy — and their work has now been published in the Journal of Rehabilitation Medicine.

They asked 335 people who had been living with MS for about 15 years to rank the activities most important to them. These activities were reported to be “getting out and about, spending time with family and friends, managing bills and expenses, and participating in clubs and civic and political events.”

By finding out what people with MS enjoy doing, or who they enjoy visiting, researchers could narrow down what was keeping them from engaging in their favourite activities, as well as with others. The results revealed that “struggling with impairments, like MS fatigue and cognitive and walking problems… inadequate social support and transportation issues… impede a person’s confidence.” Lack of confidence also influenced how well people with MS manage their symptoms.

Put another way: physical impairments, lacking support, and environmental factors act as barriers between those with MS and health and happiness. Researchers explained that not being able to overcome these barriers could possibly lead to secondary symptoms, “like depression, deconditioning from lack of exercise, and poor nutrition or eating choices that may result in obesity or diabetes.”

The study suggests it would be beneficial to people if treatments also focus on their mental health.

Matthew Plow, the study’s lead author, said in a press release that it would be worthwhile to test an intervention designed to boost people's confidence levels, which may equip them to make any changes and learn new skills in order to engage more with their community.

Primary Source: Plow M, et al. Correlates of Participation in Meaningful Activities Among People with Multiple Sclerosis. Journal of Rehabilitation Medicine, July 2015

Source: Medical Daily © 2015 Medical Daily (27/07/15)

New software can help brain lesion detection (27/07/15)
Australian scientists say they have made a significant breakthrough in the treatment and detection of multiple sclerosis (MS).

New software developed at the Royal Melbourne Hospital has been shown to assist doctors in the detection of brain lesions caused by MS and could lead to a much earlier detection of brain tumours and a myriad of other diseases.

Hospital director of research Frank Gaillard said finding the right treatment for MS patients was crucial.

He said painstaking processes involved looking through hundreds of scans, comparing old and new images to find new lesions.

"It's similar to having a couple of Dalmatians running around and trying to spot if either of them has an extra dot or not," Dr Gaillard said.

He said the technology developed at the hospital could detect minute changes in the brain in patients with MS.

"Instead of having to look at 200 lesions and identify one that might be new ... your attention is drawn to the one that wasn't present before," he said.

"Now, because there are changes in the physiology and position and how the scans are obtained ... areas ... show up that aren't real.

"The job of the radiologist, instead of being one trying to identify the lesions, is ... to use our normal clinical skills in assessing whether that lesion is actually a demyelinating lesion or caused by something else."

He said the new technology, which is already being used in live scans, could tell doctors whether a treatment was working or not long before symptoms associated with an inappropriate drug started to appear.

James Zahra was in his early 20s when he was diagnosed with the incurable disease seven years ago.

"I woke up one morning, I'd lost the use of the left side of my face and my eyesight in my left eye had diminished by about 90 per cent," he said.

"It wasn't as much of a shock as you'd think ... I was young and didn't really know anything about it.

"But people around me were a lot more scared than I was."

Mr Zahra has been on a number of different drugs over the years and described much of his treatment as trial and error.

He welcomed the Australian-first technology.

"If the machine can do what they claim it does, then fortunately for us, they can treat us appropriately," he said.

"If something is early detected they can jump on it faster before it does affect us.

"To know what's going to happen before it actually happens gives us all a solid head start."

Source: ABC News © ABC 2015 (27/07/15)

Masitinib 'shows promise' in treating MS (27/07/15)
Progressive multiple sclerosis patients treated with AB Science’s lead compound AB07002 (masitinib) in a Phase III clinical trial showed positive results in a non futility test (a test to determine if an experimental therapy shows some sign of efficacy).

With the successful completion of the futility analysis, AB Science is set to continue the remainder of the double-blind, randomized, placebo-controlled study.

“We are very pleased with this outcome as our three on-going Phase III studies in neurology, in progressive forms of multiple sclerosis, in Alzheimer’s disease, and in amyotrophic lateral sclerosis, are all non futile,” stated Alain Moussy, CEO and co-founder of AB Science, in a news release from the company.

“This was not obvious since those three indications have remained so far a challenge for the pharmaceutical industry. This may be indicative of the potential of masitinib for the treatment of neurodegenerative disorders.”

In a futility analysis, a compound is tested in patients to see if it is unable to achieve the defined efficacy objectives of the study. If the compound is declared non futile, then the researchers conducting the trial can continue with the trial because there is reason to believe the compound will achieve its efficacy objectives. A medication to treat forms of progressive multiple sclerosis would be a huge win, as there are no on-label, clinically approved medications for progressive multiple sclerosis patients.

“This positive outcome of the futility test is good news because there is no registered treatment in this indication,” said Professor Ramió-Torrentà, a lead investigator in the trial at Dr. Josep Rueta University Hosptial in Spain.

“All drugs registered in relapsing forms of multiple sclerosis, recently or not, have failed so far to demonstrate efficacy in the progressive forms of multiple sclerosis. Furthermore, masitinib is not an immunosuppressive drug, unlike drugs used in relapsing forms of multiple sclerosis.”

In the 96-week trial, patients with primary progressive or relapse-free secondary progressive multiple sclerosis are being treated with masitinib, a selective tyrosine kinase inhibitor. The compound can control the survival, migration, and degranulation of mast cells by inhibiting key cell signaling pathways. This indirectly controls the amount of proinflammatory and vasoactive mediators release in the nervous system that contribute to disease characteristics.

After one third of patients enrolled for the trial were treated for a total of 48 weeks (halfway through the trial, with an intended full enrollment of 600 patients), they were assessed for changes in the Multiple Sclerosis Functional Composite (MSFC), Multiple Sclerosis Quality of Life 54 Items (MSQOL-54), and changes in the Expanded Disability Status Scale (EDSS). The observed changes were significant enough for masitinib to be declared non futile by the Independent Data Safety Monitoring Committee (IDMC). There were also no major or unexpected adverse events that affected the safety of patients, indicating that the Phase III clinical trial is justified to continue forward.

Source: Multiple Sclerosis News Today © BioNews Services 2015 (27/07/15)

Optical coherence tomography supported in monitoring MS (24/07/15)
Rates of ganglion cell + inner plexiform layer (GCIP) atrophy mirrors that of whole brain atrophy in multiple sclerosis (MS), as measured by optimal coherence tomography (OCT), according to a study published in the Annals of Neurology.

In order to validate the utility of OCT as an indicator of neuronal tissue damage in patients with MS, Shiv Saidha, M.B.B.Ch., from Johns Hopkins University in Baltimore, and colleagues examined whether atrophy of specific retinal layers and brain substructures are associated over time. They performed biannual cirrus high definition OCT in 107 patients with MS.

The researchers observed a correlation between rates of GCIP and whole-brain, grey matter (GM), white matter (WM), and thalamic atrophy. There was a stronger correlation for GCIP and whole-brain atrophy rates in progressive versus relapsing-remitting MS (RRMS). In RRMS, the correlation between rates of GCIP and whole-brain (and GM and WM) atrophy increased incrementally with step-wise refinement to exclude ON (eyes with a past history of optic neuritis) effects; the correlation increased to 0.45 and 0.60, respectively, excluding eyes and then patients, consistent with effect modification. Lesion accumulation rate correlated with GCIP and inner nuclear layers atrophy rates in RRMS.

"Our findings support OCT for clinical monitoring and as an outcome in investigative trials," the authors write.

Source: Medical Xpress © Medical Xpress 2011 - 2015, Science X network (24/07/15)

Identifying MS gene mutations could lead to personalised treatments (24/07/15)
Personalised medicine, often applied to treat cancer, may be possible for patients with multiple sclerosis as well. Certain patients respond differently to certain multiple sclerosis medications, such as interferon-β (IFNβ), and researchers at San Raffaele Scientific Institute in Milan may have an answer as to why.

The team, led by Federica Esposito, MD, PhD, found that multiple sclerosis patients with a specific mutation in the gene SLC9A9 have more frequent relapses despite treatment with IFNβ.

“A proportion of multiple sclerosis patients experience disease activity despite treatment,” wrote Dr Esposito, explaining the motivation behind the study.

“The early identification of the most effective drug is critical to impact long-term outcome and to move toward a personalised approach.”

To achieve this goal, the research team looked for associations between multiple sclerosis patient gene expression and response to treatment with IFNβ. The researchers’ findings, published in Annals of Neurology and entitled, “A Pharmacogenetic study Implicates SLC9a9 in Multiple Sclerosis Disease Activity,” demonstrated that a genetic mutation in the gene SLC9a9, namely the rs9828519G variant, can be used to predict how multiple sclerosis patients will respond to treatment.

“Exploring the function of this gene, we see that SLC9A9 mRNA expression is diminished in multiple sclerosis subjects who are more likely to have relapses,” noted Dr Esposito. When the research team used patient-derived T cells to study the effects of SLC9A9 gene expression on IFN, they saw an increase in the pro-inflammatory molecule IFNγ.

The new information in this study may be able to screen multiple sclerosis patients for efficacious disease therapies. For example, if a patient carries a mutation in SLC9A9 that prevents its transcription into mRNA, that patient may not be well suited for IFNβ and may be a candidate for a different treatment option.

The idea is similar to that of MSPrecise, best described by an article published in Gene, MSPrecise: A Molecular Diagnostic Test For Multiple Sclerosis Using Next Generation Sequencing. This screen also finds mutations in DNA, specifically in cerebrospinal fluid-derived B cells that express a VH4 gene. Clinicians have shown it accurately identifies 84 per cent of patients who develop relapsing-remitting multiple sclerosis (RRMS). If used together, a clinician may be able to determine if an individual has RRMS via MSPrecise, then determine if IFNβ is a suitable treatment by testing for SLC9A9 mutations.

At present, currently approved multiple sclerosis therapies are developed to treat a wide range of patients and are tested on diverse patient populations in order to determine if they are relatively effective in treating the disease in across a broad clinical population. However, as the human DNA is decoded and gene mutations are better understood, the more possible it becomes to tailor future MS therapies to maximise therapeutic value for each individual patient.

Source: Multiple Sclerosis News Today © BioNews Services 2015 (24/07/15)

Anxiety 'linked to gender in multiple sclerosis' (22/07/15)
Researchers in Canada have been investigating what role gender has to play in patients with MS having anxiety and depression.

The team from Sunnybrook Health Sciences Centre in Toronto led by Dr Anthony Feinstein conducted a large retrospective study that was published in Multiple Sclerosis Journal comparing the rates of depression and anxiety across genders in MS.

According to previous studies, nearly half of all individuals living with MS will experience a major bout of depression at some point during their lifetime and are three times more likely than people without MS to suffer from anxiety.

Large population studies of non-MS individuals have consistently found higher rates of anxiety and depression in women compared to men.

Information from a behavioural database of 711 individuals with a confirmed MS diagnosis collected from 1997 to 2014 was analysed. The data included symptoms of anxiety and depression, which were scored using the Hospital Anxiety and Depression Scale, HADS. The researchers compared rates and levels of anxiety and depression between males and females.

The team found that within the MS population, women had higher overall anxiety scores than men and were more often considered clinically anxious (scoring eight or more on HADS). In contrast, frequency and severity of depressive symptoms were no different between men and women with MS.

The researchers found that gender can influence rates and levels of anxiety, but not depression, in people living with MS. Rates of anxiety were found to be higher in women, while depression was on par between the genders.

The findings suggest that the factors underpinning anxiety and depression in MS are not only different but, in the case of depression, are distinct from the general population (where women are reported to have higher levels of depression than men).

The study suggests the high rates of depression observed in MS are, therefore, not simply an artifact of gender bias within the MS population. Rather, the increased rates of depression within the MS group relative to the general population could be linked to gender-neutral changes in the brain and/or immune system common to MS.

As MS is so often characterised by gender differences, understanding the similarities and differences in common symptoms between women and men will allow for better insight and individualised therapeutic strategies, the researchers concluded.

Original Source
Théaudin M et al. (2015). In multiple sclerosis anxiety, not depression, is related to gender. Multiple Sclerosis Journal. DOI: 10.1177/1352458515588582.

Source: MS Society of Canada © 2015 MS Society of Canada (22/07/15)

Lesion location 'matters in MS' (22/07/15)
An observational clinical imaging study is claiming that cortical lesions (CLs) are associated with cognitive and physical disability in multiple sclerosis (MS), independent of white matter lesion volume.

Researchers also say they found leukocortical and subpial lesion subtypes have differing clinical relevance.

The study also points to high-field MRI as a highly effective tool for quantifying cortical pathology in MS, something which could eventually lead to more effective treatments, Daniel M. Harrison, MD, department of neurology, University of Maryland School of Medicine in Baltimore, and colleagues reported online in JAMA Neurology.

"Our finding that CL volume predicts cognitive impairment independent of white matter (WM) lesion volume or atrophy supports the notion that assessments of inflammatory WM pathology alone provide an insufficient appraisal of the pathology responsible for disability in MS," said Harrison.

"Furthermore, our findings of CL volume as an independent predictor of cognitive impairment highlights the need to determine whether current disease-modifying drugs reduce CL formation."

If these drugs do not modify CL formation, he added, "...this research may spur the development of novel therapeutics capable of reducing CLs and their associated disability."

Since the low sensitivity of 1.5-T and 3-T MRI techniques for identification of CLs has been established, high-field MRI should be integrated into future MS research and clinical trials, emphasised Harrison. "Although the availability of 7-T MRI at present limits this approach," he acknowledged, "our data show it is feasible to perform clinical-quality, whole-brain imaging in reasonable scan time and to quantify clinically relevant pathology."

Source: MedPage Today © 2015 MedPage Today, LLC (22/07/15)

Firm focuses on venom-based paediatric MS treatment (21/07/15)
Nutra Pharma, a US-based biotechnology company specialising in the acquisition, licensing, and commercialisation of pharmaceutical products and technologies for the management of neurological disorders, cancer, autoimmune, and infectious diseases, has announced it has filed an application with the US Food and Drug Administration (FDA) for orphan drug status for its investigational drug RPI-78M as a treatment for paediatric multiple sclerosis (MS).

If the orphan drug designation is granted to RPI-78M, it would provide the company with a seven-year period of market exclusivity in the US upon receiving FDA approval.

The FDA Orphan Drug Designation program provides orphan status to drugs and biologics, which are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases/disorders that affect fewer than 200,000 people in the U.S., or that affect more than 200,000 persons but are not expected to recover the costs of developing and marketing a treatment drug.

In the US, it is easier to gain marketing approval for an orphan drug, and there may be other financial incentives, such as extended exclusivity periods intended to encourage the development of drugs, and the waiver of Prescription Drug User Fee Act (PDUFA) filing fees, which can offer savings of up to $2.5 million.

Nutra Pharma chairman and CEO Rik Deitsch said in a statement: “In May, we announced that we had engaged consultants to prepare several FDA applications for us as we start to re-engage our clinical platform. We have worked hard over the past year to restructure our Company, introduce a unique and effective OTC pet pain product, and now we are getting back to our roots as a biotechnology company. We have a broad product platform that consists of therapies for auto-immune diseases, viral diseases and neurological conditions.”

As for future goals of the company, Deitsch added: “Our goal now is to get our drug products through the approval process and into the market. It is very exciting that we are starting with this application that has the potential to help children suffering from MS.”

According to Nutra Pharma, venoms are an effective source of molecular tools that are able to improve the cell function understanding. The company also mentioned that the approval of some neurotoxins as human treatments has provided new opportunities for the treatment of MS.

RPI-78M induces gamma-interferon and interleukin-27 (IL-27). IL-27 is a recently discovered and important anti-inflammatory regulator in cells of the immune system. The drug was derived from a cobra venom extract and works as a nicotinic acetylcholine receptor antagonist. The drug has been found to have low toxicity with a very large therapeutic window. RPI-78M is to able Improve quality of life, reduces chronic fatigue, improve walking ability and strength.

Source: Multiple Sclerosis News Today © BioNews Services 2015 (21/07/15)

Children ‘recover well’ from demyelination, study finds (21/07/15)
Most children can expect a good and quick physical recovery following acute central nervous system demyelination, study findings suggest.

Although a serious illness, which resulted in 86 per cent of the 283 children studied being hospitalised for three to ten days, 254 (90 per cent) of 281 children available for five-year follow-up examination had recovered fully; 209 within three months and a further 39 by 12 months.

Among the 27 (10 per cent) patients who did not experience full neurological recovery from their incident acquired demyelination syndrome, 12 had severe residual visual, motor, bowel and bladder deficits. All of these children had moderate or severe deficits at presentation and those with transverse myelitis and optic neuritis were most affected.

Multiple sclerosis (MS) was diagnosed in 59 (21 per cent) of the participants within 12 months of the incident attack and more than half of these experienced a second attack in the first year. Nevertheless, all of them recovered full mobility, normal vision and bowel and bladder control within 12 months of their incident attack and the majority within three months. Six of the MS patients, despite recovering fully from their incident attack, had subsequent relapses and developed deficits a median of 5.9 years later that persisted for at least a year.

Researcher Julia O’Mahony, from the University of Toronto, and co-workers note in Paediatrics that MS was not associated with a poor outcome. All affected children recovered and were more likely to have milder deficits at acute demyelination onset than the 224 patients with monophasic disease even when the 69 with acute disseminated encephalomyelitis were excluded.

Moderate or severe deficits in vision, motor, bladder and bowel function or cognition during the incident attack were seen in 184 children, with 41 profoundly encephalopathic, 129 unable to ambulate independently and 59 with optic neuritis.

The 102 children with transverse myelitis and those with the acute disseminated encephalomyelitis phenotype were the most likely to have moderate or severe deficits at onset, as were children younger than 12 years of age. However, the researchers observe that age did not predict residual physical impairment from the acute attack, which they say suggests “a strong capacity for neurologic repair of acute lesions in the youngest patients”.

The team concludes that their findings indicate a recovery of gait, vision and bladder and bowel function in most patients following acquired demyelination syndrome, but they do not account for the cognitive effects of the condition, future deficits in which remain a possibility.

Source: Copyright 2000-2015 Limited (21/07/15)

Study claims long duration of MS associated with higher mortality (21/07/15)
A study published in the journal PLoS One revealed an excess mortality rate among French patients with multiple sclerosis (MS) that experience the disease for more than 20 years. The study was conducted by researchers at several institutes and hospitals in France, and is entitled “Excess Mortality in Patients with Multiple Sclerosis Starts at 20 Years from Clinical Onset: Data from a Large-Scale French Observational Study.”

Researchers conducted a large-scale, observational, multicenter study (SURVIMUS) to analyse the specific mortality rate associated with MS in France. In total, 27,603 MS patients (mean age at onset of 33 years) were assessed in terms of life expectancy, mortality rates, causes of death, and prognostic factors in comparison to the French general population. All patients analysed had clinical onset of the disease at least one year prior to the study.

The team found that 1,569 (5.7 per cent) patients succumbed during the follow-up period of the study (mean 15.2 years), with half of the mortalities being related to MS. The mortality rate was found to be significantly higher among men, in patients with progressive MS, and patients with later clinical onset. Researchers also observed that the excess mortality rates were moderate in comparison to the general population, although after 20 years of disease, excess mortality increased significantly among MS patients.

The research team concluded that in this French cohort, MS patients have a moderate decrease in life expectancy by approximately seven years in comparison to the general population. In addition, the mortality rate was found to be strongly correlated to the patient’s disability and disease duration, with patients living with the disease for more than 20 years having an excess mortality rate. The team emphasised that an early intervention is required to slow disability progression and offer an extended life expectancy in MS patients.

While insights such as these may seem discouraging to the MS patient population, the findings from the SURVIMUS study are in fact helpful to researchers in focusing research efforts to develop next-generation MS therapies. Given that the study reveals that excess mortality occurs 20 years after disease onset, researchers underscore the need to slow down the progression of the disease. With novel experimental therapies focusing on neuroprotection and myelin regeneration, there are promising therapeutic approaches moving through the MS drug development pipeline that will further decrease MS progression, which in turn may lower mortality rates caused by the disease.

Source: Multiple Sclerosis News Today © BioNews Services 2015 (21/07/15)

Psychosocial factors ‘influence pain in MS’ (20/07/15)
Pain is prevalent in 63 per cent of patients with multiple sclerosis (MS), according to a recent study, and psychosocial factors may be key contributors to the severity of that pain.

A study using a cognitive-behavioural MS model suggested psychosocial factors may increase pain in patients. However, is there actually a correlation? A team from the King’s College Hospital in the UK explored the possibility.

“MS-associated pain is typically classified as either neuropathic or non-neuropathic in origin,” the authors wrote in the European Journal of Neurology. “Between five per cent and 32 per cent of patients regard pain as their most severe symptom.”

A total of 612 patients with MS filed out a survey assessing pain and ways of thinking. The severity of the disease and pain interference was determined using hierarchical regressions. Results were similar between neuropathic and non-neuropathic pain groups.

“All psychosocial factors including distress, negative beliefs about pain and its consequences, and avoidance of activity, were related to pain outcomes,” the team confirmed.

A news release explained that 85 per cent of the patients ranked as moderate to severe on the Brief Pain Inventory Short Form – even though 93 per cent were taking pain medications. After taking demographic and other variables into consideration, it was found that the psychosocial factors contributed to 24 per cent of the variance in pain severity and 30 per cent of interference. These indications remained even after disregarding conditions like depression and anxiety.

Furthermore, demographic variables made up 19 per cent of pain contribution and 26 per cent was credited to disease factors.

“The team points out that patients with more severe and interfering pain had more pain catastrophizing,” the statement continued, “were likely to view pain as being persistent over time with serious consequences and tended to avoid social and physical activities.”

It was concluded that psychosocial factors are important predictors for pain levels and can help with determining effective treatment.

Source: MS All Specialities Copyright MD Magazine 2006-2015 Intellisphere, LLC (20/07/15)

Study finds lesions may compromise heart rate in Gilenya patients (20/07/15)
In a recent study published in the Journal PLOS One, a team of researchers found that the autonomic cardiovascular dysfunction in MS patients with delayed heart rate re-acceleration upon Gilenya-initiation suggest MS-related central autonomic lesions may compromise heart rate re-acceleration.

Gilenya causes the heart rate to slow even in healthy people and may also cause prolonged or more prominent heart rate slowing in some MS patients. Results from phase III clinical trials showed Gilenya caused bradycardia and serious cardiovascular adverse events, including atrioventricular blocks.

The European Medicines Agency (EMA) recommends that upon Gilenya initiation, patients should have their heart rate monitored for at least six hours or if it is at the lowest value six hours following the first dose, extended monitoring for at least two more hours and until the heart rate increases again.

It remains unclear why some patients with MS have prolonged heart rate slowing, or why some develop atrioventricular blocks or bradycardia.

In their study, Central Autonomic Dysfunction Delays Recovery Of Fingolimod (Gilenya) Induced Heart Rate Slowing, Ralf A. Linker from the Department of Neurology, University of Erlangen-Nuremberg, Erlangen in Germany and colleagues hypothesised that autonomic dysfunction, such as the sympathetic-parasympathetic imbalance and Gilenya-induced bradycardia are due to pathophysiology of the central control and adjustment of cardiovascular autonomic modulation.

Based on this assumption, the team of researchers examined whether standard autonomic cardiovascular testing is able to indicate central autonomic cardiovascular dysfunction prior to initiation of Gilenya in MS patients who need more than six hours after Gilenya-initiation to re-increase their heart rate.

The researchers recorded electrocardiographic RR-intervals (RRIs) and blood-pressure (BP) at rest, upon standing-up, during metronomic deep-breathing before Gilenya-initiation in a population of 21 patients with relapsing-remitting MS, and in 20 healthy controls.

The results revealed that upon Gilenya-initiation, seven patients had prolonged heart rate slowing. Prior to the initiation of Gilenya, the seven patients were found to have a higher resting BP and also a higher BP increase during handgrip-exercise in comparison with the other participants. The results also showed that the patients did not reduce parasympathetic heart rate parameters upon standing-up. After Valsalva-strain-release exercise the researchers found that the patients parasympathetic heart rate slowing in response to BP-overshoot was four times higher than in the other participants.

The researchers indicate the need for further studies comparing cardiovascular autonomic modulation of MS patients on Gilenya and patients on other disease modifying treatment which might be helpful to further strengthen this study findings.

Source: Multiple Sclerosis News Today © BioNews Services 2015 (20/07/15)

Second case of Tecfidera PML reported (17/07/15)
Biogen Idec has reported another case of progressive multifocal leukoencephalopathy (PML) in a patient taking Tecfidera (dimethyl fumarate) to the FDA.

PML is a rare infection of the brain that occurs in people who have compromised immune systems and have been infected with the John Cunningham (JC) virus. PML is also known to occur in patients taking Tysabri.

Only a few details about this new patient have been being released, but it is reported to be “non-fatal” and the patient has been diagnosed with primary progressive multiple sclerosis. The patient also had prolonged severe lymphopenia, which is recognised in the label for Tecfidera as a potential risk for PML.

This new case is similar to the first reported case of PML in a patient who was taking Tecfidera. In the first reported case, the patient was a 54-year-old woman with MS who had a severe case of lymphopenia for three and a half years.

Tecfidera has been on the market in the US since early 2013. A representative of Biogen Idec said she does not anticipate any label changes to the drug at this time, but physicians should be vigilant about prolonged severe lymphopenia.

Source: © 2012-15 Health Union, LLC (17/07/15)

New MS factor found (17/07/15)
Research published in the Journal of Immunology claims the cytokine granulocyte macrophage colony stimulating factor (GM CSF) could be involved in multiple sclerosis (MS) progression and development.

Researchers from Thomas Jefferson University in Philadelphia first examined prior studies on the subject, which debated the exact function of GM CSF in MS. They aimed to determine the mechanisms behind the brain inflammation and loss of neurological function that are hallmarks of MS.

“After our animal studies showed GM CSF was important in the development of an MS-like condition, we were excited to see these results confirmed using samples from MS patients in the current study,” study author Abdolmohamad Rostami, MD, PhD, explained in a press release.

The Th 17 cell was identified by MS researchers a number of years ago as a key player in causing the neuronal damage of MS, the statement continued. The Th 17 cells produce cytokine IL 17, hinting to the researchers that IL 17 was essential to MS – even though many studies indicate it is not. The research team published a study in 2011 stating that Th 17 cells also produce GM CSF in mice models. That research demonstrated that in animal models of MS, mice that could not produce GM CFS did not develop MS. However, mice models who lacked IL 17 did develop MS (but it was a mild form of the disease).

The new research aimed to elucidate if the same observations would be true in blood samples from human MS patients who were naïve to any therapies, alongside those who were being treated with INF beta (a commonly used therapy, the researchers noted). The untreated patients had between two and three times as many immune cells producing GM CSF than the INF beta patients or normal non MS subjects that were tested.

In the brains of deceased MS patients, the team found increased numbers of GM CFS producing cells compared to the normal brain (non MS) samples.

“The study demonstrates a new mechanism of action for INF beta therapies,” Rostami continued. “We hope that this research showing GM CFS is an important target will lead us toward therapies that more effectively block the damaging immune reaction in the central nervous system of MS patients.”

The statement added that a recent Phase 1 clinical trial of a GM CFS blocking drug showed early signs of effect – but highlighted the fact that Phase 1 trials are only designed to test the safety of a new drug, not its efficacy. The authors continued that GM CFS treatment is worth pursuing, though, based on the Phase 1 trial and their own research.

Source: MD All Specialities Copyright MD Magazine 2006-2015 Intellisphere, LLC (17/07/15)

Study reveals exercise benefits mental health (15/07/15)
In a recent study published in the International Journal of Molecular Sciences, a team of researchers from Germany have identified an association between increased physical activity and improved mental health in patients with multiple sclerosis (MS).

In the study titled Mental Health In Multiple Sclerosis Patients Without Limitation Of Physical Function: The Role Of Physical Activity, Mathias Mäurer from the Caritas Krankenhaus Bad Mergentheim gGmbH in Uhlandstr, Germany and colleagues assessed a total of 632 MS patients using the Baecke questionnaire on physical activity, the Short Form 36 Health Survey (SF-36), and Beck Depression Inventory (BDI).

The Baecke questionnaire is a survey of habitual physical activity (e.g., sport), ranging from one (lowest activity) to five (highest activity), which is used in epidemiological studies.

The results showed that active and inactive patients did not differ considerably in physical function. In contrast, mental subscales of the SF-36 were higher in active patients. Remarkable and significant differences were found regarding vitality, general health perception, social functioning and mental health, all in favour of physically active patients.

Based on these results, the researchers concluded that physical activity and exercise have a considerable health benefit for MS patients and, consequently, should represent an essential part of successful symptom management in MS therapy, especially in early disease stages.

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

Nano-drugs could treat multiple sclerosis (15/07/15)
Nano-drugs encased in liposomes could one day be used to treat neurological conditions like multiple sclerosis (MS), according to a new study published in the journal, PloS One. A liposome is a small, fat-soluble droplet that can contain a water soluble drug.

It is thought liposomes might be useful for treating neurological conditions because fat-soluble molecules can cross the blood-brain barrier, a blockade that protects the nervous system from the blood.

The researchers, based in Israel, used liposome-based nano-drugs to deliver drugs to the nervous system of mice that had been treated to have a form of experimental MS, called experimental autoimmune encephalomyelitis (EAE).

A common problem with conventional medications is that they are broken down too quickly by the body or they do not arrive at the site that they are intended to treat. Liposomal nano-drugs could help solve this problem by dissolving more slowly, and also by arriving at the site that requires treatment, specifically the nervous system. They could cross the blood-brain barrier, particularly useful for diseases that affect the brain and spinal cord. Furthermore, liposomal drug delivery could allow for more targeted drug delivery, requiring less active medication and resulting in fewer side-effects.

In the study, the researchers used two types of drugs, including methylprednisolone and Tempamine (TMN), delivered using the liposomal nano-method. According to their findings, “it was demonstrated that these nano-drugs ameliorate the clinical signs and the pathology of EAE [experimental MS].” The drugs reduced brain damage in the animal model, and also diminished movement problems that occur in these animals, which are similar to the movement problems found in MS. The medications also lasted longer in the blood before being broken down.

The authors further remarked that “the highly efficacious anti-inflammatory therapeutic feature of these two nano-drugs meets the criteria of disease-modifying drugs and supports further development and evaluation of these nano-drugs as potential therapeutic agents for diseases with an inflammatory component.”

Liposomal nano-drugs could provide a new way to deliver many old medications, improving the effectiveness and the delivery of existing drugs. Further studies in humans are of course needed.

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

Study claims Tysabri improves cognitive impairment (14/07/15)
Researchers in Italy have published findings claiming Tysabri (natalizumab) can improve cognitive impairment in patients with relapsing remitting multiple sclerosis (RRMS) over the course of at least three years.

In the study, Natalizumab Significantly Improves Cognitive Impairment Over Three Years In MS: Pattern Of Disability Progression And Preliminary MRI Findings, researchers at the Spedali Civili of Brescia investigated the impact of Tysabri treatment on cognitive impairment in a cohort of 24 patients with RRMS who were treated for three years. Patients were assessed through neuropsychological tests and in terms of relapse rate and expanded disability status scale (EDSS) score.

Researchers found that after three years of Tysabri treatment, a significant reduction in the number of impaired neuropsychological tests was achieved, along with a considerable decrease in annualized relapse rate and a stable EDSS in comparison to baseline. A particular significant improvement was found in memory, attention and executive function test scores.

The team also analysed brain cortical atrophy in a patient subgroup through magnetic resonance imaging (MRI). Preliminary results showed that after three years of Tysabri treatment there were no alterations in grey matter volume but a significantly greater parahippocampal and prefrontal grey matter density, which correlated with the neuropsychological improvement observed.

The research team concluded that Tysabri therapy can reduce cognitive impairment in RRMS patients in a long-term period of three years. The team suggests that Tysabri most likely has a neuroprotective role concerning cortical grey matter in the brain.

The findings were published in the journal PLoS One.

Source: Multiple Sclerosis News Today © BioNews Services 2015 (14/07/15)

Study claims dice loaded for patients with late-stage MS (09/07/15)
People living with multiple sclerosis have the dice loaded against them when it comes to their decision-making ability as their condition progresses, according to a new study from the University of Alberta's Faculty of Medicine & Dentistry.

"About half of people with MS will experience cognitive defects or limitations in that capacity. Decision-making becomes important to look at in these populations," said lead author Ashley Radomski, who completed the research as part of her master's thesis.

In the study, published in BMC Neurology, people with MS took part in an assessment that involved throwing dice, which has been shown in other studies to be a standard determinant of explicit risk.

The test, The Game of Dice Task (GDT), challenges study participants to evaluate risks associated with throwing dice by choosing a combination of one, two, three or four digits as a predicted outcome of each roll. More numbers in a chosen combination means a less risky choice, but also means lower rewards for a correct guess—which, Radomski explained, can lure participants to make less advantageous choices that reveal their everyday decision-making capacity.

Esther Fujiwara, Radomski's supervisor and an associate professor in the Department of Psychiatry, helped develop the test as part of her own PhD studies. "People with MS are faced with many complex decisions on a regular basis—for example, choices about which medications to take or not take, what short- or long-term effects are desirable or undesirable, which side-effects seem acceptable or unacceptable, and so on," Fujiwara notes.

"What we found in our study is that those patients who have increased disease severity, as indicated by a particular subtype of MS or by greater structural changes in the brain, did have greater decision-making disabilities than patients who were considered less severe," Radomski said.

People with MS or their family members may find it helpful to keep a journal to help identify decision-making patterns over time, suggested Radomski, who emphasised that the journal should be discussed with the patient's doctor, nurse or neurologist for a full assessment.

Radomski also noted the rules of GDT were explained to participants at the beginning of the task, and remained consistent and on display throughout the rounds. GDT was administered as part of a two-hour standardised neuropsychological test battery to evaluate the participants' working and verbal memory, visual-spatial abilities and motor function, among other traits.

Fujiwara hopes to continue this research by examining whether stress, which has a major role in MS, affects decisions made by people living with MS more than people without MS.

"Knowing that decision-making can suffer in later-stage MS, we need to make sure to provide optimal guidance and support in making such complex decisions, and especially so for individuals in more advanced stages of the disease," she said.

Source: Medical Xpress © Medical Xpress 2011-2015, Science X network (09/07/15)

Mitochondria ‘may play role in MS progression’ (09/07/15)
Recent attention to the role of mitochondria in the cause of multiple sclerosis suggests mitochondrial defects and mitochondrial structural and functional changes may contribute to the condition. Researchers studying mitochondria in multiple sclerosis believe abnormalities in mitochondrial dynamics impact cellular pathways such as inflammation and demyelination, ultimately impacting patients with multiple sclerosis.

Dr Peizhong Mao and Dr P Hemachandra Reddy, of the Neurogenetics Laboratory at Oregon Health & Science University, identified five key abnormalities in the mitochondria that are involved in disease development and progression. Mitochondrial DNA defects, abnormal mitochondrial gene expression, defective mitochondrial enzyme activities, deficient mitochondrial DNA repair activity, and mitochondrial dysfunction have been shown to play a role, according to the two researchers’ article, Is Multiple Sclerosis A Mitochondrial Disease? that was published in Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease.

“Neurons are highly dependent on oxidative energy metabolism,” wrote Dr Mao and Dr Reddy.

“Deficient mitochondrial metabolism may generate more reactive oxygen species (ROS) that can wreak havoc in the cell.”

A recent study published in Neurology, entitled Mitochondrial DNA Sequence Variation In Multiple Sclerosis, demonstrated certain mitochondrial genetic variants are associated with multiple sclerosis. For example, patients with haplogroup J variants were at a 1.5-times increased risk for developing primary progressive multiple sclerosis.

Another look into mitochondrial involvement in multiple sclerosis was conducted by Dr Lukas Haider at the Medical University of Vienna.

“Recent data indicates that mitochondrial injury and subsequent energy failure are key factors in the induction of demyelination and neurodegeneration,” wrote Dr Haider in the article Inflammation, Iron, Energy Failure And Oxidative Stress In The Pathogenesis Of Multiple Sclerosis, which was published in Oxidative Medicine and Cellular Longevity.

Since the brain accounts for such a large proportion of oxygen consumption in the mitochondria, cells in the brain are especially susceptible to oxidative stress, leading to the previously identified genetic variants as a result of damage. Without properly functioning mitochondria, cells within the brain cannot thrive.

Dr Mao and Dr Reddy discussed a few therapeutic approaches to treat multiple sclerosis by targeting the mitochondria. These therapies are considered more neuroprotective than immunomodulatory and are different from current treatments for multiple sclerosis. Inhibitors of proteins that allow oxidative stress to damage the mitochondria, such as intravenous mitoxantrone, might delay the progression of multiple sclerosis in relapsing-remitting or secondary progressive multiple sclerosis.

Enhancing mitochondrial DNA repair by targeting repair proteins to the mitochondria may also prove to be an effective means for treating multiple sclerosis, while also addressing the direct problem of mitochondrial dysfunction in the disease. At present, mitochondria-targeted antioxidants such as MitoQ can help address oxidative stress in the development of diseases such as Multiple Sclerosis by decreasing mitochondrial oxidative damage. Ubiquinone, the active ingredient in MitoQ, is identical to Coenzyme Q10, a well-known antioxidant. Some researchers believe that therapies such as these offer a novel approach to addressing the underlying cause of MS, and patients have reported it success in improving symptoms and quality of life as an alternative the currently FDA-approved multiple sclerosis therapies.

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

Breakdown in brain communication discovered (08/07/15)
New findings published in Neuropsychology reveal decreased connectivity between network-specific brain regions are to blame for the central deficit common to the various cognitive changes associated with multiple sclerosis.

In the first study of its kind, researchers at the Centre for BrainHealth at The University of Texas at Dallas and The University of Texas Southwestern Medical Centre found that, compared to healthy controls, individuals with MS exhibit weaker brain connections between the dorsolateral prefrontal cortex and posterior brain regions. The change amounts to a breakdown in communication between the part of the brain responsible for executing goal-directed thought and action and the regions responsible for carrying out tasks related to cognitive speed such as visual processing, motor execution, and object recognition.

The researchers believe the diminished connections are likely to be the result of decreased white matter surrounding the neurons in the brain.

"Our study is the first to really zero in on the physiology of cognitive speed, the central cognitive deficit in MS," explained principal investigator Bart Rypma, PhD.

"While white matter is essential to efficient network communication, white matter degradation is symptomatic of MS. This study really highlights how tightly coupled connectivity is to performance and illuminates the larger, emerging picture of white matter's importance in human cognitive performance."

Collaborating with Elliot Frohman, MD, PhD, director of the Multiple Sclerosis Program and Clinical Centre at UT Southwestern, the study recruited 29 participants with relapsing-remitting MS and 23 age- and sex- matched healthy controls. Participants underwent functional magnetic resonance imaging (fMRI) while completing a measure of cognitive processing speed.

Participants were given four seconds to view a nine-item key of number and symbol pairs (for example '+' above the number 3) and one number-symbol pair probe. Participants were asked to indicate with a left or right thumb button press whether or not the probe appeared in the key.

While accuracy was similar for both healthy controls and individuals with MS, response times for individuals with MS were much slower. Analysis of the fMRI data revealed that while completing this measure, MS patients showed weaker functional connections with dorsolateral prefrontal cortex.

"These findings reveal a diffuse pattern of disconnectivity with executive areas of the brain," explained the study's lead author, Nicholas Hubbard.

"Importantly, these decreases in connectivity predicted MS-related cognitive slowing both in and out of the fMRI environment suggesting that these results were not specific to our task, but rather were able to generalize to other situations where cognitive speed is required."

This research supports the need for therapies that target white matter structures and white matter proliferation. Rypma and Hubbard are currently conducting research to further explore the physiology of white matter to better understand cognitive speed reductions not only in MS, but also in healthy aging individuals.

Source: EurekaAlert! Copyright © 2015 by the American Association for the Advancement of Science (AAAS) (08/07/15)

Researchers find key neuropathic pain trigger (08/07/15)
Scientists at the University of California, Davis, have identified a key mechanism in neuropathic pain. The discovery could benefit millions of patients with chronic pain from trauma, diabetes, shingles, multiple sclerosis or other conditions that cause nerve damage.

A biological process called endoplasmic reticulum stress, or ER stress, is the significant driver of neuropathic pain, said lead researchers Bora Inceoglu of the UC Davis Department of Entomology and Nematology and UC Davis Comprehensive Cancer Centre, and Ahmed Bettaieb, Department of Nutrition. The work is published July 6 in the journal Proceedings of the National Academy of Sciences.

“This is a fundamental discovery that opens new ways to control chronic pain,” said co-author Bruce Hammock, distinguished professor at the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Centre.

“We can now specifically search for agents to control ER stress and its downstream pathways,” Hammock said. “This search is already underway in a number of laboratories working on cancer and other diseases.”

Working with Professor Fawaz Haj of the UC Davis nutrition department, Bettaieb found that key molecular signatures associated with diabetes and diabetic pain were linked to ER stress. Neuropathic pain is a common consequence of both Type 1 and Type 2 diabetes, affecting up to 70 percent of patients.

Inceoglu, working in Hammock’s laboratory, showed neuropathic pain could be initiated by compounds that cause ER stress and reversed by agents that block it.

The researchers had previously shown that a class of natural bioactive lipids has powerful analgesic effects in the body. These analgesic lipids are broken down in the body by an enzyme, soluble epoxide hydrolase. The team was able to show that blocking soluble epoxide hydrolase blocks ER stress and associated neuropathic pain.

The work sheds new light onto at least one biological process that mediates neuropathic pain, Inceoglu said. With this knowledge, researchers can now test ER-stress blocking drugs in the clinic, and carry out fundamental research on how different types of pain grouped under the name “neuropathic” differ from each other and respond to new drugs.

The study provides convincing evidence for a novel concept as to what causes neuropathic pain said John Imig, professor of pharmacology and toxicology at the Medical College of Wisconsin, Milwaukee, who was not involved in the study. The work provides new opportunities for drugs or drug combinations to treat chronic pain, he said.

Source: UCDavis Copyright © The Regents of the University of California, Davis campus (08/07/15)

Bacteria “biofilm” mystery investigated (07/07/15)
Lupus, multiple sclerosis, and type-1 diabetes are among more than a score of diseases in which the immune system attacks the body it was designed to defend. But just why the immune system begins its misdirected assault has remained a mystery.

Now, researchers at Temple University School of Medicine (TUSM) have shown that bacterial communities known as biofilm play a role in the development of the autoimmune disease systemic lupus erythematosus -- a discovery that may provide important clues about several autoimmune ailments.

A team led by TUSM researchers Çagla Tükel, PhD, and Stefania Gallucci, MD, show how bacterial biofilms found in the gut can provoke the onset of lupus in lupus-prone mice. The research is published in the current issue of the journal Immunity.

Dr Tükel is an Assistant Professor of Microbiology and Immunology at TUSM, and Dr Gallucci is Associate Chair, Microbiology and Immunology, as well as an Associate Professor in Microbiology and Immunology at TUSM. Both are members of the Temple Autoimmunity Centre.

"This work stresses the importance of considering infections as a possible trigger for lupus," Dr Gallucci said. "Very little was known about how biofilms interact with the immune system because most of the research has been looking at how biofilms protect bacteria, how they make bacteria resistant to antimicrobials such as antibiotics, but almost nothing was known about what biofilms do to the immune response.”

Biofilm is a densely packed bacterial community that excretes proteins and other substances. Those substances form a matrix that protects the bacteria from antimicrobials, the immune system, and other stressors. Biofilms can occur in our guts, among the bacteria that help us digest. They exist as dental plaque, or arise in urinary tract infections. They also can find a home on man-made surfaces such as intravenous catheters. Central to the lupus story is a biofilm protein deposit called an amyloid. In the common gut bacteria E. coli, as well as the bacteria often responsible for severe gastrointestinal distress that accompanies food poisoning, Salmonella Typhimurium, amyloids are called curli because of their curly fibre-like appearance.

Also part of the biofilm is DNA excreted by bacteria. The Temple team discovered that when curli amyloids and DNA meet, they form remarkably durable bonds in the biofilm. When the researchers attempted to separate the DNA from these bonds using a variety of enzymes as well as chemicals, the curli wouldn't let go. Curli-DNA complexes speed up the creation of the biofilm, the researchers learned. And the Temple researchers found it is also in this composite of curli-plus-DNA that autoimmune trouble appears to arise.

The new research shows that the complexes formed from curli amyloid and DNA in the biofilms of both Salmonella and E. coli give rise to not only inflammation, but the self-attacking antibodies of lupus and other such conditions.

To demonstrate the role of biofilms in immune response, the researchers wanted to see how the sentinels of the immune system, called dendritic cells, reacted to a biofilm. The dendritic cells sent "tendrils" into the biofilm and ate up part of it to signal other molecules. Further, they produced large amounts of chemicals called proinflammatory cytokines. These cytokines are important in inciting the immune system to act. Among the cytokines was Type-1 interferon, known to be associated with lupus.

"I was super excited when I saw how activated the dendritic cells were on the biofilm " Dr Gallucci said. The levels of cytokines released when dendritic cells were exposed to curli-DNA complexes actually exceeded the most robust response known previously -- the response to lipopolysaccharide (LPS).

To test if the immune response seen in the laboratory would be enough to induce autoimmunity and the attack on self that occurs in lupus, the researchers used mice that are prone to develop autoimmune disease. As is the case with many diseases, lupus is the result of a genetic propensity that lies dormant in the absence of an environmental trigger. The researchers wanted to see if the curli-DNA complexes could provide that trigger. They injected susceptible mice with the amyloid-DNA composites or a placebo. Within two weeks, the researchers found the kind of antibodies that attack "self," known as autoantibodies. The autoantibodies, which target double-stranded DNA, are a diagnostic hallmark of lupus. The response was remarkably fast. It normally takes mice four to five months to develop autoantibodies.

Another strain of mice that do not develop lupus spontaneously but are genetically predisposed to autoimmunity also reacted to the curli-DNA composites with rapid production of autoantibodies. A third strain of mice with no propensity for any autoimmune disease, developed autoantibodies within two weeks of injection, but at lower levels than in the mice with a propensity toward lupus.

All mice developed the autoantibodies whether the curli-DNA composites came from Salmonella or from the kind of E. coli that's found in a healthy digestive system. In fact, three of the four bacterial families that contain curli genes are found in the gut: Bacteroidetes, Proteobacteria, and Firmicutes, suggesting a possible source of vulnerability in susceptible patients. "How that happens, I think that will be the next level of our project," Dr Gallucci said. The research team is already looking at mouse models to see what may lead to the escape of curli-DNA complexes from the gut. Further, the team is collaborating with rheumatologist Dr Roberto Caricchio, Director of the Temple Lupus Clinic, to see if the patients show signs of exposure to the curli-DNA complexes.

"The next step is to explore the mechanism of how these composites are stimulating autoimmunity," Dr Tükel said. "The beneficial bacteria found in our guts can cause problems when they cross the intestinal barrier and reach to places they shouldn't be. Thus, besides infectious bacteria, a leaky gut could cause many problems. We are now starting to understand how the bacteria in our gut may trigger complex human diseases including lupus. So it's critical for us to understand the biology of the bacterial communities and their interactions with the immune system."

The research may offer clues to diseases involving amyloids, Dr Tükel said. For instance, amyloid plaques in the brain are a signature of Alzheimer's disease. Type-2 diabetes and Parkinson's disease also feature amyloids. "Right now, we can only speculate," she said. "Some reports suggested that antibiotic treatment may be changing the course of Alzheimer's disease. Antibiotics are thought, in some cases, to slow the mental decline suggesting that bacterial infections, or a bacterial component, may be contributing to the disease. That could be a link, but for the moment, it's only speculation."

Understanding how biofilms trigger autoimmunity may ultimately lead to changes in patient treatment, Dr Gallucci said. "So understanding how the biofilms affect flares could lead to a different treatment approach. Now, they give immune suppressive drugs. Maybe you want to do something else, like treat the underlying infection."

Source: EurekaAlert! Copyright © 2015 by the American Association for the Advancement of Science (AAAS) (07/07/15)

American Society funds grant to explore new MS pathology model (02/07/15)
America’s National Multiple Sclerosis Society has provided a grant to a Wayne State University School of Medicine professor to explore a new model of MS pathology.

Alexander Gow, Ph.D., the Charles H. Gershenson Distinguished Fellow Professor and associate director of the WSU Centre for Molecular Medicine and Genetics, will use the three-year, $663,959 grant for his study Neurodegeneration Associated With Metabolic Stress In Oligodendrocytes.

From the early-mid phases of MS, Dr Gow said, the clinical symptoms are caused by damage to the brain in the forms of autoimmune lesions, atrophy in the white matter and grey matter of the brain and cognitive deficits. So far most studies have focused on finding disease-modifying therapies for the autoimmune component of MS, but have tended to ignore the cognitive changes.

Several important findings have come to light in recent years, he said, including the revelation that strong immunosuppression of patients for several years only modestly slows MS progression while damage to cortical brain regions continues.

“In this study, we tackle both of these issues using a new model of MS pathology that does not involve autoimmune stimulation to generate disease symptoms,” said Dr Gow, who also is a professor of Paediatrics and of Neurology for WSU. “Rather, we activate metabolic stress in oligodendrocytes to cause dysfunction and death of these cells, which is a potential disease mechanism that has gained experimental support from several laboratories.”

Oligodendrocytes are a type of cell that produce a membrane called myelin that coats axons, the pathways by which the brain sends messages to the muscles.

Dr Gow will seek to determine whether this nonimmune-mediated animal model can recapitulate MS pathology and whether he can find evidence for behavioural changes and cognitive decline. He also will test a drug treatment designed to protect oligodendrocytes and neurons from the degenerative changes associated with inducing primary metabolic stress.

There is increasing evidence, Dr Gow said, to indicate autoimmune attacks on the central nervous system may be a secondary event rather than the primary cause of MS. This indicates researchers must cast a broader net to test new ideas and develop alternative models that could shed fresh light on MS aetiology.

Source: Newswise ©2015 Newswise, Inc (02/07/15)