Background:
Multiple sclerosis (MS) is a complex disease with new drugs becoming available in the past years. There is a need for a reference tool compiling current data to aid professionals in ...treatment decisions.
Objectives:
To develop an evidence-based clinical practice guideline for the pharmacological treatment of people with MS.
Methods:
This guideline has been developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology and following the updated EAN recommendations. Clinical questions were formulated in Patients–Intervention–Comparator–Outcome (PICO) format and outcomes were prioritized. The quality of evidence was rated into four categories according to the risk of bias. The recommendations with assigned strength (strong and weak) were formulated based on the quality of evidence and the risk-benefit balance. Consensus between the panelists was reached by use of the modified nominal group technique.
Results:
A total of 10 questions were agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease-modifying drugs approved by the European Medicine Agency (EMA) at the time of publication. A total of 21 recommendations were agreed by the guideline working group after three rounds of consensus.
Conclusion:
The present guideline will enable homogeneity of treatment decisions across Europe.
The accumulation of β-amyloid (Aβ) peptide in the brain is one of the pathological hallmarks of Alzheimer's disease and is thought to be of primary aetiological significance. In an unbiased genetic ...screen, we identified puromycin-sensitive aminopeptidase (PSA) as a potent suppressor of Aβ toxicity in a Drosophila model system. We established that coexpression of Drosophila PSA (dPSA) in the flies' brains improved their lifespan, protected against locomotor deficits, and reduced brain Aβ levels by clearing the Aβ plaque-like deposits. However, confocal microscopy and subcellular fractionation of amyloid-expressing 7PA2 cells demonstrated that PSA localizes to the cytoplasm. Therefore, PSA and Aβ are unlikely to be in the same cellular compartment; moreover, when we artificially placed them in the same compartment in flies, we could not detect a direct epistatic interaction. The consequent hypothesis that PSA's suppression of Aβ toxicity is indirect was supported by the finding that Aβ is not a proteolytic substrate for PSA in vitro. Furthermore, we showed that the enzymatic activity of PSA is not required for rescuing Aβ toxicity in neuronal SH-SY5Y cells. We investigated whether the stimulation of autophagy by PSA was responsible for these protective effects. However PSA's promotion of autophagosome fusion with lysosomes required proteolytic activity and so its effect on autophagy is not identical to its protection against Aβ toxicity.
•PSA is a potent suppressor of Aβ toxicity and reduces brain Aβ levels in flies.•PSA is cytoplasmic but there is no direct epistatic interaction with Aβ in vivo.•Aβ is not a proteolytic substrate for PSA in vitro.•The enzymatic activity of PSA is not required for rescuing Aβ toxicity in cells.•PSA stimulates autophagy but this is unlikely to be the mechanism that suppresses Aβ toxicity.
Multiple sclerosis (MS) is one of the world's most common neurologic disorders, and in many countries it is the leading cause of nontraumatic neurologic disability in young adults. Despite this, ...global information on the epidemiology of MS and the availability of resources and services for people with MS is scarce in many regions of the world. The first Atlas of MS, published in 2008 as a joint project of the Multiple Sclerosis International Federation (MSIF) and the World Health Organization (WHO), super(1) endeavored to fill this knowledge gap with information from 112 countries. Here, we outline important updates in the recently launched Atlas of MS 2013: Mapping Multiple Sclerosis around the World. super(2)
Despite significant progress in the development of therapies for relapsing MS, progressive MS remains comparatively disappointing. Our objective, in this paper, is to review the current challenges in ...developing therapies for progressive MS and identify key priority areas for research. A collaborative was convened by volunteer and staff leaders from several MS societies with the mission to expedite the development of effective disease-modifying and symptom management therapies for progressive forms of multiple sclerosis. Through a series of scientific and strategic planning meetings, the collaborative identified and developed new perspectives on five key priority areas for research: experimental models, identification and validation of targets and repurposing opportunities, proof-of-concept clinical trial strategies, clinical outcome measures, and symptom management and rehabilitation. Our conclusions, tackling the impediments in developing therapies for progressive MS will require an integrated, multi-disciplinary approach to enable effective translation of research into therapies for progressive MS. Engagement of the MS research community through an international effort is needed to address and fund these research priorities with the ultimate goal of expediting the development of disease-modifying and symptom-relief treatments for progressive MS.
The Multiple Sclerosis International Federation (MSIF), established in 1967, links the activities of more than 85 national MS societies worldwide. Over those 45 years, and particularly in the last ...20, it has seen dramatic changes in our understanding, treatment, and multidisciplinary management of people with MS. However, these advances are not universal and there are embarrassing discrepancies in the levels of treatment and care provided in different parts of the world. MSIF's research strategy is guided by an International Medical and Scientific Board composed of 70 experts in MS, nominated by our member organizations and incorporating an Executive Committee. Our strategy focuses on areas that might benefit from a global approach, those that are newly emerging, and those that are particularly challenging. We encourage young investigators to enter the field of MS research, and particularly support those from underdeveloped countries to facilitate transfer of knowledge and expertise from more "expert" areas. Our current portfolio focuses on progressive MS, pediatric MS, and stem cell therapy.
A major function of proteasomes and macroautophagy is to eliminate misfolded potentially toxic proteins. Mammalian proteasomes, however, cannot cleave polyglutamine (polyQ) sequences and seem to ...release polyQ-rich peptides. Puromycin-sensitive aminopeptidase (PSA) is the only cytosolic enzyme able to digest polyQ sequences. We tested whether PSA can protect against accumulation of polyQ fragments. In cultured cells, Drosophila and mouse muscles, PSA inhibition or knockdown increased aggregate content and toxicity of polyQ-expanded huntingtin exon 1. Conversely, PSA overexpression decreased aggregate content and toxicity. PSA inhibition also increased the levels of polyQ-expanded ataxin-3 as well as mutant α-synuclein and superoxide dismutase 1. These protective effects result from an unexpected ability of PSA to enhance macroautophagy. PSA overexpression increased, and PSA knockdown or inhibition reduced microtubule-associated protein 1 light chain 3-II (LC3-II) levels and the amount of protein degradation sensitive to inhibitors of lysosomal function and autophagy. Thus, by promoting autophagic protein clearance, PSA helps protect against accumulation of aggregation-prone proteins and proteotoxicity.
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