This Week's Multiple Perspectives In Multiple Sclerosis (MPMS)

• Mapping progress of MS. Researchers show that inflammatory processes drive multiple sclerosis disease, leading to ‘amplification cycle’ that furthers neurodegeneration. This opens up new avenues for treatment, including initial targeted treatment for the initial inflammation, in addition to shedding light on disease pathogenesis. 
• TREM2 the rescue. A new protein, TREM2, might help slow disease progression by aiding microglia, a key immune cell in the CNS, in clearing plaques in Alzheimers and myelin fragments in multiple sclerosis. Understanding the key molecules and processes that help ‘clean’ the brain are fundamental to learning how to manage damage in the CNS. 
• Exercise prescriptions. A new study suggests that targeted balance-training prescriptions can help with managing balance deficits in MS. This study highlights the importance of developing individual treatment goals to maintain mobility.
• New molecule may limit inflammation. A new molecule, MCC950, has been shown to inhibit inflammatory processes that may play a role in diseases like multiple sclerosis. The benefits of MCC950 would be great since it can be given orally and can be cleared more quickly from the body, which would allow for clearance of infections if needed.
• Want to know who is funding clinical trials? Many participants do. According to a new study published online in Multiple Sclerosis Journal, patients would like to know about funding sources as part of the informed consent of clinical trials. This is not just important to highlight potential conflict of interests, but also highlight the need to develop clear guidelines about proper disclosure. 

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Multiple Perspectives In Multiple Sclerosis (MPMS) is written by Brittany Goods and reviewed and edited by Deborah Backus PhD

MAPPING PROGRESS OF MS

• Link to news article: http://www.sciencedaily.com/releases/2015/02/150209083509.ht
• Original journal reference: Don H Mahad, Bruce D Trapp, Hans Lassmann. Pathological mechanisms in progressive multiple sclerosis. The Lancet Neurology, 2015; 14 (2): 183 DOI: 10.1016/S1474-4422(14)70256-
• Abstract: A better understanding of the pathological mechanisms that drive neurodegeneration in individuals with multiple sclerosis is needed to develop therapies that will effectively treat patients in the primary and secondary progressive stages of the disease. We propose that the inflammatory demyelinating disease process in early multiple sclerosis triggers a cascade of events that lead to neurodegeneration and are amplified by pathogenic mechanisms related to brain ageing and accumulated disease burden. Key elements driving neurodegeneration include microglia activation, chronic oxidative injury, accumulation of mitochondrial damage in axons, and age-related iron accumulation in the human brain. Altered mitochondrial function in axons might be of particular importance. This process leads to chronic cell stress and imbalance of ionic homoeostasis, resulting in axonal and neuronal death. The evidence suggests that treatment of progressive multiple sclerosis should be based on a combination of anti-inflammatory, regenerative, and neuroprotective strategies.

 TREM2 To The Rescue

• Link to news article: http://www.sciencedaily.com/releases/2015/03/150302091654.htm
• Original journal reference: TREM2 Lipid Sensing Sustains the Microglial Response in an Alzheimer’s Disease Model. http://www.cell.com/cell/abstract/S0092-8674(15)00127-
• Abstract: Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor that triggers intracellular protein tyrosine phosphorylation. Recent genome-wide association studies have shown that a rare R47H mutation of TREM2 correlates with a sub- stantial increase in the risk of developing Alzheimer’s disease (AD). To address the basis for this genetic as- sociation, we studied TREM2 deficiency in the 5XFAD mouse model of AD. We found that TREM2 deficiency and haploinsufficiency augment b-amyloid (Ab) accumulation due to a dysfunctional response of mi- croglia, which fail to cluster around Ab plaques and become apoptotic. We further demonstrate that TREM2 senses a broad array of anionic and zwitter- ionic lipids known to associate with fibrillar Ab in lipid membranes and to be exposed on the surface of damaged neurons. Remarkably, the R47H mutation impairs TREM2 detection of lipid ligands. Thus, TREM2 detects damage-associated lipid patterns associated with neurodegeneration, sustaining the microglial response to Ab accumulation.

Exercise prescriptions.

• Link to article: http://www.medicalnewstoday.com/releases/282900.php
• Original study: http://www.jcomjournal.com/case-based-reviewunderstanding-and-treating-balance-impairment-in-multiple-sclerosis/
• Abstract: Understanding and Treating Balance Impairment in Multiple Sclerosis Objective: To provide insight into the mechanisms and treatment options associated with balance impairments in individuals with multiple sclerosis (MS). Methods: Systematic reviews, randomized controlled trials, and noncontrolled studies were examined to collect current data regarding treatment options aimed at improving balance in MS. Results: Balance deficits are common in individuals with MS and result from a diverse set of constraints across multiple systems of postural control. Poor balance often leads to increased fall risk, reduced physical activity, added comorbidities, and decreased quality of life. A variety of exercise options are available for individuals with MS who experience balance and mobility problems. Physical interventions include targeted therapies, such as vestibular rehabilitation and weighted torso training, as well as more general exercise and balance training prescriptions. Conclusion: The evidence, albeit preliminary, suggests that therapeutic intervention aimed at ameliorating balance deficits associated with MS be multimodal. Exercise prescriptions should include sensory and motor strategy training, strength development, as well as functional gait activities. Further evidence-based research is needed to improve the management of balance deficits in those with MS and to identify the impact of improved balance on activity participation and quality of life.

New molecule may limit inflammation.

• Link to article: http://multiplesclerosisnewstoday.com/2015/03/02/multiple-sclerosis-treatments-benefit-from-discovery-of-new-inflammatory-molecule/
• Original study: http://www.nature.com/nm/journal/v21/n3/full/nm.3806.html 
• Abstract: The NOD-like receptor (NLR) family, pyrin domain–containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer’s disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1b (IL-1b) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle–Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease. 

Want to know who is funding clinical trials? Many participants do...

• Link to article: http://www.sciencedaily.com/releases/2015/02/150227130914.htm
• Original Study: Patient perspectives on physician conflict of interest in industry-sponsored clinical trials for multiple sclerosis therapeutics.
• Abstract: Background: Pharmaceutical industry financial support of physicians, physician practices, and academic departments involved in multicenter industry-sponsored clinical trials of novel therapeutic agents is a relatively new and infrequently acknowledged source of potential physician conflict of interest. Detailed disclosure of these relationships to study participants is not uniformly a part of informed consent and documentation practices. Objective: To understand attitudes of patients with multiple sclerosis concerning disclosure of potential physician-industry conflicts of interest created by clinical trials and how such disclosures may influence study participation METHODS: An anonymous online instrument was developed. Results: 597 people with multiple sclerosis participated in the study. The study found that detailed disclosure of conflicts of interest is important to potential participants in industry-sponsored clinical trials for multiple sclerosis therapies and that the presence of these conflicts of interest may influence patients' decisions to participate in these studies. Conclusions: Findings from this study support a call for uniform guidelines regarding disclosure of physician-industry relationships to prospective research participants for industry-sponsored clinical trials.