Lipidomic UPLC-MS/MS Profiles of Normal-Appearing White Matter Differentiate Primary and Secondary Progressive Multiple Sclerosis

Multiple sclerosis (MS) is a neurodegenerative inflammatory disease where an autoimmune response to components of the central nervous system leads to a loss of myelin and subsequent neurological deterioration. People with MS can develop primary or secondary progressive disease (PPMS, SPMS) and differentiation of the specific differences in the pathogenesis of these two courses, at the molecular level, is currently unclear. Recently, lipidomics studies using human biofluids, mainly plasma and cerebrospinal fluid, have highlighted a possible role for lipids in the initiation and progression of MS. However, there is a lack of lipidomics studies in MS on CNS tissues, such as normal-appearing white matter (NAWM), where local inflammation initially occurs. Herein, we developed an untargeted reverse phase ultra-performance liquid chromatography time of flight tandem mass spectrometry (RP-UPLC-TOF MSE)-based workflow, in combination with multivariate and univariate statistical analysis, to assess significant differences in lipid profiles in brain NAWM from post-mortem cases of PPMS, SPMS and controls. Groups of eight control, nine PPMS and seven SPMS NAWM samples were used. Correlation analysis of the identified lipids by RP-UPLC-TOF MSE was undertaken to remove those lipids that correlated with age, gender and post-mortem interval as confounding factors. We demonstrate that there is a significantly altered lipid profile of control cases compared with MS cases and that progressive disease, PPMS and SPMS, can be differentiated on the basis of the lipidome of NAWM with good sensitivity, specificity and prediction accuracy based on receiver operating characteristic (ROC) curve analysis. Metabolic pathway analysis revealed that the most altered lipid pathways between PPMS and SPMS were glycerophospholipid metabolism, glycerophosphatidyl inositol (GPI) anchor synthesis and linoleic acid metabolism. Further understanding of the impact of these lipid alterations described herein associated with progression will provide an increased understanding of the mechanisms underpinning progression and highlight possible new therapeutic targets

The use of vibrational spectroscopy to study the pathogenesis multiple sclerosis and other neurological conditions

Spectroscopy techniques are valuable tools in biomedical research and have been used extensively in the study of disease. However, neurological conditions such as multiple sclerosis (MS) have received little attention and the available spectroscopy studies are limited, both in overall numbers of patients studied and the disease samples considered. MS is a complex immune-mediated disease, with variable clinical courses and limited therapeutic options. This review aims to summarize current literature in the area, demonstrating how spectroscopy techniques can provide valuable information to inform and advance research into the most common neurological condition affecting young adults

Family-focused campus-based university event increases perceived knowledge, science capital and aspirations across a wide demographic

Creative ways of delivering informal science events in community settings are viewed as key to engaging new audiences and participants whom scientists find hard to reach, however, the impact of ‘formal’ setting events is often overlooked. Here, through a mixed-methods approach, we analyse a large-scale family-focused public engagement event hosted within a university campus setting. We aimed to explore the profile of visitors attending together with the impact and perceived knowledge gained. Analysis from two consecutive years of data collection found that the university-based event attracted new visitors annually, with almost half having not attended other science events/attractions within the last year. An increase in perceived knowledge was shown amongst all study participants, being significantly amplified in those from low progression to higher education postcode areas. Both immediate and longer-term positive impact was reported by participants with increases in components of science capital observed as well as enhanced positive perception of the university and its students. This data exemplifies the benefit of university-hosted events in widening participation and public understanding of science

Transcriptome analysis suggests a role for the differential expression of cerebral aquaporins and the MAPK signalling pathway in human temporal lobe epilepsy

Epilepsies are common disorders of the central nervous system (CNS), affecting up to 2% of the global population. Pharmaco-resistance is a major clinical challenge affecting about 30% of temporal lobe epilepsy (TLE) patients. Water homeostasis has been shown crucial for regulation of neuronal excitability. The control of water movement is achieved through a family of small integral membrane channel proteins called aquaporins (AQPs). Despite the fact that changes in water homeostasis occur in sclerotic hippocampi of people with TLE, the expression of AQPs in the epileptic brain is not fully characterised. This study uses microarray and ELISA methods to analyse the mRNA and protein expression of the human cerebral AQPs in sclerotic hippocampi (TLE-HS) and adjacent neocortex tissue (TLE-NC) of TLE patients. The expression of AQP1 and AQP4 transcripts was significantly increased, while that of the AQP9 transcript was significantly reduced in TLE-HS compared to TLE-NC. AQP4 protein expression was also increased while expression of AQP1 protein remained unchanged, and AQP9 was undetected. Microarray data analysis identified 3,333 differentially regulated genes and suggested the involvement of the MAPK signalling pathway in TLE pathogenesis. Proteome array data validated the translational profile for 26 genes and within the MAPK pathway (e.g. p38, JNK) that were identified as differentially expressed from microarray analysis. ELISA data showed that p38 and JNK inhibitors decrease AQP4 protein levels in cultured human primary cortical astrocytes. Elucidating the mechanism of selective regulation of different AQPs and associated regulatory proteins may provide a new therapeutic approach to epilepsy treatment. This article is protected by copyright. All rights reserved

Qualitative investigation of exercise perceptions and experiences in people with multiple sclerosis before, during, and after participation in a personally tailored exercise program

Objective To undertake a qualitative investigation of exercise perceptions and experiences in people with multiple sclerosis (PwMS) before, during, and after participation in a personally tail ored program designed to promote long-term maintenance of self-directed exercise. Design Focus groups and semistructured telephone interviews. Setting University exercise science department close to the recruiting hospital. Participants PwMS (N=33; mean age ± SD, 47.6±7.9y). Interventions Participants were recruited after participation in a randomized controlled exercise trial; all had been allocated to a 12-week exercise program comprising supervised and self-directed exercise sessions. Main Outcome Measures Exercise perceptions and experiences before, during, and after participation in the program. Results Four themes emerged from the analysis: (1) the transition to inactivity; (2) lack of knowledge and confidence; (3) positive exercise experiences; and (4) perspectives on exercise adherence. Conclusions Lack of confidence and exercise knowledge, coupled with negative perceptions about physical capabilities after an MS diagnosis, are clear barriers to exercise participation in PwMS. These issues are not being adequately addressed as part of the health care pathway or in community settings. Perceptions of improved posture, ability to overcome everyday difficulties, acute mood enhancements during and after exercise, and increased opportunities for social interaction were among the reported benefits of exercise participation. Despite the provision of a personally tailored exercise plan and use of cognitive behavioral strategies, self-directed exercise continued to present challenges to PwMS, and the importance of seeking cost-effective ways to maintain motivational support was implicit in participant responses

Study protocol to investigate the effect of a lifestyle intervention on body weight, psychological health status and risk factors associated with disease recurrence in women recovering from breast cancer treatment

Background Breast cancer survivors often encounter physiological and psychological problems related to their diagnosis and treatment that can influence long-term prognosis. The aim of this research is to investigate the effects of a lifestyle intervention on body weight and psychological well-being in women recovering from breast cancer treatment, and to determine the relationship between changes in these variables and biomarkers associated with disease recurrence and survival. Methods/design Following ethical approval, a total of 100 patients will be randomly assigned to a lifestyle intervention (incorporating dietary energy restriction in conjunction with aerobic exercise training) or normal care control group. Patients randomised to the dietary and exercise intervention will be given individualised healthy eating dietary advice and written information and attend moderate intensity aerobic exercise sessions on three to five days per week for a period of 24 weeks. The aim of this strategy is to induce a steady weight loss of up to 0.5 Kg each week. In addition, the overall quality of the diet will be examined with a view to (i) reducing the dietary intake of fat to ~25% of the total calories, (ii) eating at least 5 portions of fruit and vegetables a day, (iii) increasing the intake of fibre and reducing refined carbohydrates, and (iv) taking moderate amounts of alcohol. Outcome measures will include body weight and body composition, psychological health status (stress and depression), cardiorespiratory fitness and quality of life. In addition, biomarkers associated with disease recurrence, including stress hormones, estrogen status, inflammatory markers and indices of innate and adaptive immune function will be monitored. Discussion This research will provide valuable information on the effectiveness of a practical, easily implemented lifestyle intervention for evoking positive effects on body weight and psychological well-being, two important factors that can influence long-term prognosis in breast cancer survivors. However, the added value of the study is that it will also evaluate the effects of the lifestyle intervention on a range of biomarkers associated with disease recurrence and survival. Considered together, the results should improve our understanding of the potential role that lifestyle-modifiable factors could play in saving or prolonging lives

Localisation of citrullinated proteins in normal appearing white matter and lesions in the central nervous system in multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease, considered to be autoimmune in origin. Post-translational modification of central nervous system proteins, including glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP), through citrullination of arginine residues, may lead to exposure of neoepitopes, triggering autoimmunity. Here we investigated the expression of citrullinated proteins in active MS lesions, MS normal appearing white matter and control brain white matter. We demonstrate increased citrullinated GFAP and MBP by immunohistochemistry and western blotting in areas of ongoing demyelination, suggesting a pivotal role for deimination of GFAP and MBP in MS pathogenesis MS

Participant recruitment into a randomised controlled trial of exercise therapy for people with multiple sclerosis

The success of a clinical trial is often dependant on whether recruitment targets can be met in the required time frame. Despite an increase in research into the benefits of exercise in people with multiple sclerosis (PwMS), no trial has reported detailed data on effective recruitment strategies for large-scale randomised controlled trials. The main purpose of this report is to provide a detailed outline of recruitment strategies, rates and estimated costs in the Exercise Intervention for Multiple Sclerosis (ExIMS) trial to identify best practices for future trials involving multiple sclerosis (MS) patient recruitment

Gene expression profiling of the astrocyte transcriptome in multiple sclerosis normal appearing white matter reveals a neuroprotective role

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS). White matter lesions in MS are surrounded by areas of non-demyelinated normal appearing white matter (NAWM) with complex pathology, including blood brain barrier dysfunction, axonal damage and glial activation. Astrocytes, the most abundant cell type within the CNS, may respond and/or contribute to lesion pathogenesis. We aimed to characterise the transcriptomic profile of astrocytes in NAWM to determine whether specific glial changes exist in the NAWM which contribute to lesion development or prevent disease progression. Astrocytes were isolated from control and NAWM by laser capture microdissection (LCM), using glial fibrillary acidic protein (GFAP) as a marker, and the astrocyte transcriptome determined using microarray analysis. 452 genes were significantly differentially expressed (208 up-regulated and 244 down-regulated, FC ≥ 1.5 and p-value ≤ 0.05). Within the NAWM, astrocytes were associated with significant upregulation of genes involved in the control of iron homeostasis (including metallothionein-1 and -2, ferritin light chain and transferrin), oxidative stress responses, the immune response and neurotrophic support. These findings suggest a neuroprotective role of astrocytes in the NAWM in M