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Microglia activity can drive excessive synaptic loss during the prodromal phase of Alzheimer's disease (AD) and is associated with lowered cyclic adenosine monophosphate (cAMP) due to cAMP phosphodiesterase 4B (PDE4B). This study aimed to investigate whether long-term inhibition of PDE4B by A33 (3 mg/kg/day) can prevent synapse loss and its associated cognitive decline in APPswe/PS1dE9 mice. This model is characterized by a chimeric mouse/human APP with the Swedish mutation and human PSEN1 lacking exon 9 (dE9), both under the control of the mouse prion protein promoter. The effects on cognitive function of prolonged A33 treatment from 20 days to 4 months of age, was assessed at 7–8 months. PDE4B inhibition significantly improved both the working and spatial memory of APPswe/PSdE9 mice after treatment ended. At the cellular level, in vitro inhibition of PDE4B induced microglial filopodia formation, suggesting that regulation of PDE4B activity can counteract microglia activation. Further research is needed to investigate if this could prevent microglia from adopting their 'disease-associated microglia (DAM)' phenotype in vivo. These findings support the possibility that PDE4B is a potential target in combating AD pathology and that early intervention using A33 may be a promising treatment strategy for AD. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), spinal cord injury (SCI), and amyotrophic lateral sclerosis (ALS), are characterized by acute or chronic progressive loss of one or several neuronal subtypes. However, despite their increasing prevalence, little progress has been made in successfully treating these diseases. Research has recently focused on neurotrophic factors (NTFs) as potential regenerative therapy for neurodegenerative diseases. Here, we discuss the current state of knowledge, challenges, and future perspectives of NTFs with a direct regenerative effect in chronic inflammatory and degenerative disorders. Various systems for delivery of NTFs, such as stem and immune cells, viral vectors, and biomaterials, have been applied to deliver exogenous NTFs to the central nervous system, with promising results. The challenges that currently need to be overcome include the amount of NTFs delivered, the invasiveness of the delivery route, the blood–brain barrier permeability, and the occurrence of side effects. Nevertheless, it is important to continue research and develop standards for clinical applications. In addition to the use of single NTFs, the complexity of chronic inflammatory and degenerative diseases may require combination therapies targeting multiple pathways or other possibilities using smaller molecules, such as NTF mimetics, for effective treatment. [ABSTRACT FROM AUTHOR]

Supplemental digital content is available in the text. Introduction: This study examines the role of nutritional status during exercise training in patients with type 2 diabetes mellitus by investigating the effect of endurance-type exercise training in the fasted versus the fed state on clinical outcome measures, glycemic control, and skeletal muscle characteristics in male type 2 diabetes patients. Methods: Twenty-five male patients (glycated hemoglobin (HbA1c), 57 ± 3 mmol·mol−1 (7.4% ± 0.3%)) participated in a randomized 12-wk supervised endurance-type exercise intervention, with exercise being performed in an overnight-fasted state (n = 13) or after consuming breakfast (n = 12). Patients were evaluated for glycemic control, blood lipid profiles, body composition and physical fitness, and skeletal muscle gene expression. Results: Exercise training was well tolerated without any incident of hypoglycemia. Exercise training significantly decreased whole-body fat mass (−1.6 kg) and increased high-density lipoprotein concentrations (+2 mg·dL−1), physical fitness (+1.7 mL·min−1·kg−1), and fat oxidation during exercise in both groups (P TIME < 0.05), with no between-group differences (P TIME × GROUP > 0.05). HbA1c concentrations significantly decreased after exercise training (P TIME < 0.001), with a significant greater reduction after consuming breakfast (−0.30% ± 0.06%) compared with fasted state (−0.08% ± 0.06%; mean difference, 0.21%; P TIME × GROUP = 0.016). No interaction effects were observed for skeletal muscle genes related to lipid metabolism or oxidative capacity. Conclusions: Endurance-type exercise training in the fasted or fed state do not differ in their efficacy to reduce fat mass, increase fat oxidation capacity, and increase cardiorespiratory fitness and high-density lipoprotein concentrations or their risk of hypoglycemia in male patients with type 2 diabetes. HbA1c seems to be improved more with exercise performed in the postprandial compared with the postabsorptive state. [ABSTRACT FROM AUTHOR]

BACKGROUND: Persons with Multiple Sclerosis have elevated resting serum lactate concentrations compared to healthy controls (HC). OBJECTIVE: To evaluate lactate concentrations during acute exercise and/or following training in MS compared to HC. METHODS: In this retrospective study, blood lactate concentrations (mmol/l) originating from two previous studies were analyzed. Lactate concentrations originated from acute submaximal (MSsubmax; HC, n = 11; MS, n = 32) or maximal (MSmax; HC, n = 20; MS, n = 24) exercise tests and following a 24-week mild to moderate intensity (MSsubmax, n = 12) or 12-week high intensity interval (MSmax, n = 13) exercise intervention. RESULTS: Under submaximal conditions in MS and compared to HC, lactaterest (MS: 2.7±0.6 vs HC: 2.3±0.7 was significantly (p < 0.05) elevated. After 24 weeks of mild-to-moderate-intensity exercise training and compared to PRE-values, lactatebout2 (2.5±0.7 vs 3.4±1.1) significantly (p < 0.05) decreased during submaximal testing in MSsubmax. Under maximal conditions, lactatestart (2.3±1.0 vs 1.7±0.9) was significantly (p > 0.05) elevated in MS. Twelve weeks of high intensity interval training did not improve this (p > 0.05). CONCLUSIONS: Under the conditions of this retrospective analysis we conclude that lactate concentrations during acute submaximal and maximal exercise in persons with MS are similar compared to healthy controls. Moderate intensity exercise therapy appeared to improve lactate accumulation but high intensity exercise therapy did not. [ABSTRACT FROM AUTHOR]

Purpose: High-intensity concurrent training positively affects cardiovascular risk factors. Because this was never investigated in multiple sclerosis, the present pilot study explored the impact of this training on cardiovascular risk factors in this population. Methods: Before and after 12 weeks of high-intense concurrent training (interval and strength training, 5 sessions per 2 weeks, n = 16) body composition, resting blood pressure and heart rate, 2-h oral glucose tolerance (insulin sensitivity, glycosylated hemoglobin, blood glucose and insulin concentrations), blood lipids (high- and low-density lipoprotein, total cholesterol, triglyceride levels) and C-reactive protein were analyzed. Results: Twelve weeks of high-intense concurrent training significantly improved resting heart rate (−6%), 2-h blood glucose concentrations (−13%) and insulin sensitivity (−24%). Blood pressure, body composition, blood lipids and C-reactive protein did not seem to be affected. Conclusions: Under the conditions of this pilot study, 12 weeks of concurrent high-intense interval and strength training improved resting heart rate, 2-h glucose and insulin sensitivity in multiple sclerosis but did not affect blood C-reactive protein levels, blood pressure, body composition and blood lipid profiles. Further, larger and controlled research investigating the effects of high-intense concurrent training on cardiovascular risk factors in multiple sclerosis is warranted. Implications for rehabilitation: High-intensity concurrent training improves cardiovascular fitness. This pilot study explores the impact of this training on cardiovascular risk factors in multiple sclerosis. Despite the lack of a control group, high-intense concurrent training does not seem to improve cardiovascular risk factors in multiple sclerosis. [ABSTRACT FROM AUTHOR]

Background: Exercise therapy studies in persons with multiple sclerosis (pwMS) primarily focused on motor outcomes in mid disease stage, while cognitive function and neural correlates were only limitedly addressed. Objectives: This pragmatic randomized controlled study investigated the effects of a remotely supervised community-located "start-to-run" program on physical and cognitive function, fatigue, quality of life, brain volume, and connectivity. Method: In all, 42 pwMS were randomized to either experimental (EXP) or waiting list control (WLC) group. The EXP group received individualized training instructions during 12 weeks (3×/week), to be performed in their community aiming to participate in a running event. Measures were physical (VO2max, sit-to-stand test, Six-Minute Walk Test (6MWT), Multiple Sclerosis Walking Scale-12 (MSWS-12)) and cognitive function (Rao's Brief Repeatable Battery (BRB), Paced Auditory Serial Attention Test (PASAT)), fatigue (Fatigue Scale for Motor and Cognitive Function (FSMC)), quality of life (Multiple Sclerosis Impact Scale-29 (MSIS-29)), and imaging. Brain volumes and diffusion tensor imaging (DTI) were quantified using FSL-SIENA/FIRST and FSL-TBSS. Results: In all, 35 pwMS completed the trial. Interaction effects in favor of the EXP group were found for VO2max, sit-to-stand test, MSWS-12, Spatial Recall Test, FSMC, MSIS-29, and pallidum volume. VO2max improved by 1.5 mL/kg/min, MSWS-12 by 4, FSMC by 11, and MSIS-29 by 14 points. The Spatial Recall Test improved by more than 10%. Conclusion: Community-located run training improved aerobic capacity, functional mobility, visuospatial memory, fatigue, and quality of life and pallidum volume in pwMS. [ABSTRACT FROM AUTHOR]

Background: Physical rehabilitation can improve walking capacity in persons with multiple sclerosis (MS). However, changes in spatiotemporal gait parameters after rehabilitation are not frequently evaluated, and it is unknown to what extent potential effects depend on baseline disability level. The objective was to investigate the effectiveness of rehabilitation programs on gait parameters at usual and fastest speeds in persons with MS categorized according to walking speed. Methods: This nonrandomized multinational study in "real-world" settings evaluated participants before and after conventional rehabilitation. Outcome measurements included spatiotemporal gait parameters assessed by an electronic walkway (at usual and fastest speeds), walking capacity tests (Timed 25-Foot Walk test, 2-Minute Walk Test, 6-Minute Walk Test), and the patient-reported 12-item Multiple Sclerosis Walking Scale. Patients were allocated into three subgroups based on walking speed (<0.82 m/s and >1.14 m/s) and MS center. Results were calculated for the total group and subgroups. Results: Forty-two persons with MS (26 women; mean ± SD age, 44.6 ± 11.0 years; mean ± SD Expanded Disability Status Scale score, 3.5 ± 1.5) receiving rehabilitation treatment were enrolled. After rehabilitation treatment, the group demonstrated a significant decrease in double support time and an increase in stride length and step length (left leg) at usual and fastest speeds. Velocity and step length (right leg) increased only at usual speed. Subgroup analysis revealed greatest and clinically meaningful improvements in more disabled persons with MS. Conclusions: Physical rehabilitation induced changes in spatiotemporal gait parameters in persons with MS. The magnitude of improvement was greater in participants with more walking impairment. [ABSTRACT FROM AUTHOR]

Obesity-related adipose tissue (AT) dysfunction, in particular subcutaneous AT (SCAT) lipolysis, is characterized by catecholamine resistance and impaired atrial natriuretic peptide (ANP) responsiveness. It remains unknown whether exercise training improves (non-)adrenergically mediated lipolysis in metabolically compromised conditions. We investigated the effects of local combined a-/ß-adrenoceptor blockade on abdominal SCAT lipolysis in lean insulin sensitive (IS) (n=10), obese IS (n=10), and obese insulin resistant (IR) (n=10) men. Obese men participated in a 12-week exercise training intervention to determine the effects on SCAT lipolysis. Abdominal SCAT extracellular glycerol concentration and blood flow (ATBF) were investigated using microdialysis, with/without locally combined a-/ß-adrenoceptor blockade at rest, during low-intensity endurance-type exercise and post-exercise recovery. In obese IR men, microdialysiswas repeated after exercise intervention. The exercise-induced increase in SCAT extracellular glycerol wasmore pronounced in obese IS compared with lean IS men, possibly resulting from lower ATBF in obese IS men. The exercise-induced increase in extracellular glycerol was blunted in obese IR compared with obese IS men, despite comparable local ATBF. Abdominal SCAT extracellular glycerol was markedly reduced (remaining ~60% of exercise-induced SCAT extracellular glycerol) following the local a-/ß-adrenoceptor blockade in obese IS but not in IR men, suggesting reduced catecholamine-mediated lipolysis during exercise in obese IR men. Exercise training did not affect (non-)adrenergically mediated lipolysis in obese IR men. Our findings showed a major contribution of non-adrenergically-mediated lipolysis during exercise in male abdominal SCAT. Furthermore, catecholamine-mediated lipolysis may be blunted during exercise in obese IR men but could not be improved by exercise intervention, despite an improved metabolic profile and body composition. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an inflammatory auto-immune disease of the central nervous system (CNS). Serum glucose alterations and impaired glucose tolerance (IGT) are reported in MS patients, and are commonly associated with the development of cardio-metabolic co-morbidities. We previously found that a subgroup of MS patients shows alterations in their lipoprotein profile that are similar to a pre-cardiovascular risk profile. In addition, we showed that a high-intensity exercise training has a positive effect on IGT in MS patients. In this study, we hypothesize that exercise training positively influences the lipoprotein profile of MS patients. To this end, we performed a pilot study and determined the lipoprotein profile before (controls, n = 40; MS patients, n = 41) and after (n = 41 MS only) 12 weeks of medium-intensity continuous training (MIT, n = 21, ~60% of VO2max) or high-intensity interval training (HIT, n = 20, ~100-200% of VO2max) using nuclear magnetic resonance spectroscopy (NMR). Twelve weeks of MIT reduced intermediate-density lipoprotein particle count ((nmol/L); -43.4%; p < 0.01), low-density lipoprotein cholesterol (LDL-c (mg/dL); -7.6%; p < 0.05) and VLDL size ((nm); -6.6%; p < 0.05), whereas HIT did not influence the lipoprotein profile. These results show that MIT partially normalizes lipoprotein alterations in MS patients. Future studies including larger patient and control groups should determine whether MIT can reverse other lipoprotein levels and function and if these alterations are related to MS disease progression and the development of co-morbidities. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is associated with loss of skeletal muscle mass and function. The myogenic stem cells (satellite cells--SCs) are instrumental to accretion of myonuclei, but remain to be investigated in MS. The present study aimed to compare the SC and myonuclei content between MS patients (n = 23) and age matched healthy controls (HC, n = 18). Furthermore, the effects of 12 weeks of high intensity training on SC and myonuclei content were explored in MS. Muscle biopsies were obtained from m. Vastus Lateralis at baseline (MS and HC) and following 12 weeks of training (MS only). Frozen biopsies were sectioned followed by immunohistochemical analysis for fiber type specific SCs (Pax7+), myonuclei (MN) and central nuclei content and fiber cross-sectional area (fCSA) was quantified using ATPase histochemistry. At baseline the SCs per fiber was lower in type II compared to type I fibers in both MS (119%, p < 0.01) and HC (69%, p < 0.05), whereas the SCs per fCSA was lower in type II fibers compared to type I only in MS (72%, p < 0.05). No differences were observed in MN or central nuclei between MS and HC. Following training the type II fiber SCs per fiber and per fCSA in MS patients increased by 165% (p < 0.05) and 135% (p < 0.05), respectively. Furthermore, the type II fiber MN content tended (p = 0.06) to be increased by 35% following training. In conclusion, the SC content is lower in type II compared to type I fibers in both MS and HC. Furthermore, high intensity training was observed to selectively increase the SC and myonuclei content in type II fibers in MS patients. [ABSTRACT FROM AUTHOR]

Recent evidence suggests a key role of dendritic cells (DC) in the immunopathogenesis of multiple sclerosis (MS). Whereas dysfunction of DC was reported in MS patients, the underlying cause for this is not fully elucidated yet. The aim of the present study was to compare the gene expression profile of molecules involved in TLR4 and TLR7 signaling in DC from patients with MS and healthy controls. For this, circulating DC subsets were purified from patients with relapsing-remitting MS (RRMS) and from healthy controls for quantitative real-time PCR analysis. Additionally, TLR responsiveness in peripheral blood was investigated. We observed an aberrant steady-state release of IL-12p70 and IFN-α in patients with RRMS compared with healthy controls. Expression of IRF1 and JUN was reduced in conventional DC from patients with RRMS. In plasmacytoid DC from patients with RRMS, expression of IRF7 and IFNGR1 was reduced, while higher expression levels of TLR4 and LY86 were found compared with DC from healthy controls. The observed alterations in the gene expression of molecules involved in the TLR4 and TLR7 signaling pathways in circulating DC subsets may underlie the impaired IL-12p70 and IFN-α secretion in patients with RRMS, thereby potentially contributing to the disease pathogenesis of MS. [ABSTRACT FROM AUTHOR]

Background: In persons with MS (pwMS), a lower cardiopulmonary fitness has been associated with a higher risk for secondary disorders, decreased functional capacity, symptom worsening and reduced health-related quality of life. Objective: To investigate the association between disease severity and cardiopulmonary fitness. Methods: Data from cardiopulmonary exercise tests, previously conducted in three different countries, were pooled. The association between disease severity (Expanded Disability Status Scale (EDSS)) and cardiopulmonary fitness (peak oxygen uptake (VO2peak)) was adjusted for age, sex and the country of origin. Results: The combined sample comprised 116 ambulant pwMS having a mean (± SD) EDSS score of 2.7 ± 1.3. There was a significant correlation (r = -0.418, p < .01) between VO2peak and EDSS. A multiple regression model (R2 = 0.520, p < .01) was constructed to describe VO2peak (mL∙kg−1∙min−1); VO2peak = 36.622 − 5.433 (Sex (1=men)) – 0.124 (Age) − 2.082 (EDSS) + 2.737 (Belgium) + 8.674 (Denmark). Conclusion: There was a significant association between disease severity and cardiopulmonary fitness. The close relation between cardiopulmonary fitness and chronic conditions associated with physical inactivity, suggest a progressive increase in risk of secondary health conditions in pwMS [ABSTRACT FROM AUTHOR]

Previously, we reported that patients with multiple sclerosis (MS) demonstrate improved muscle strength, exercise tolerance, and lean tissue mass following a combined endurance and resistance exercise program. However, the effect of exercise on the underlying disease pathogenesis remains elusive. Since recent evidence supports a crucial role of dendritic cells (DC) in the pathogenesis of MS, we investigated the effect of a 12-week combined exercise program in MS patients on the number and function of DC. We demonstrate an increased number of plasmacytoid DC (pDC) following the exercise program. These pDC display an activated phenotype, as evidenced by increased numbers of circulating CD62L+ and CD80+ pDC. Interestingly, the number of CD80+ pDC positively correlates with the presence of IL-10-producing regulatory type 1 cells (Tr1), an important cell type for maintaining peripheral tolerance to self-antigens. In addition, decreased production of the inflammatory mediators, TNF-α and MMP-9, upon Toll-like receptor (TLR) stimulation was found at the end of the exercise program. Overall, our findings suggest that the 12-week exercise program reduces the secretion of inflammatory mediators upon TLR stimulation and promotes the immunoregulatory function of circulating pDC, suggestive for a favorable impact of exercise on the underlying immunopathogenesis of MS. [ABSTRACT FROM AUTHOR]

In healthy individuals, one exercise bout induces a substantial increase in the number of circulating leukocytes, while their function is transiently suppressed. The effect of one exercise bout in multiple sclerosis (MS) is less studied. Since recent evidence suggests a role of dendritic cells (DC) in the pathogenesis of MS, we investigated the effect of one combined endurance/resistance exercise bout on the number and function of DC in MS patients and healthy controls. Our results show a rapid increase in the number of DC in response to physical exercise in both MS patients and controls. Further investigation revealed that in particular DC expressing the migratory molecules CCR5 and CD62L were increased upon acute physical activity. This may be mediated by Flt3L- and MMP-9-dependent mobilization of DC, as demonstrated by increased circulating levels of Flt3L and MMP-9 following one exercise bout. Circulating DC display reduced TLR responsiveness after acute exercise, as evidenced by a less pronounced upregulation of activation markers, HLA-DR and CD86, on plasmacytoid DC and conventional DC, respectively. Our results indicate mobilization of DC, which may be less prone to drive inflammatory processes, following exercise. This may present a negative feedback mechanism for exercise-induced tissue damage and inflammation. [ABSTRACT FROM AUTHOR]

Recently, a supramolecular model was developed for predicting striated skeletal muscle intensity profiles obtained by label-free second harmonic generation (SHG) microscopy. This model allows for a quantitative determination of the length of the thick filament antiparallel range or M-band (M), and results in M = 0.12 μm for single-band intensity profiles when fixing the A-band length (A) to A = 1.6 μm, a value originating from electron microscopy (EM) observations. Using simulations and experimental data sets, we showed that the objective numerical aperture (NA) and the refractive index (RI) mismatch (Δn = n2ω - nω) between the illumination wave (ω) and the second harmonic wave (2ω) severely affect the simulated sarcomere intensity profiles. Therefore, our recovered filament lengths did not match with those observed by EM. For an RI mismatch of Δn = 0.02 and a moderate illumination NA of 0.8, analysis of single-band SHG intensity profiles with freely adjustable A- and M-band sizes yielded A = 1.40 ± 0.04 μm and M = 0.07 ± 0.05 μm for skeletal muscle. These lower than expected values were rationalized in terms of the myosin density distribution along the myosin thick filament axis. Our data provided new and practical insights for the application of the supramolecular model to study SHG intensity profiles in striated muscle. [ABSTRACT FROM AUTHOR]

BACKGROUND: Whole-body cooling improves exercise tolerance in patients with multiple sclerosis (pwMS). To be able to exercise at greater intensities and/or for longer durations with whole-body cooling, it should be examined whether this compromises skeletal muscle oxidative capacity (assessed by exercise-onset VO2 kinetics). OBJECTIVE: To study the impact of whole-body cooling on exercise-onset VO2 kinetics in pwMS. METHODS: From 12 pwMS (EDSS 3.5 ± 1.5) and 12 healthy age, BMI, and gender-matched subjects exercise-onset VO2 kinetics (mean response time [MRT]) and body temperature were determined under normothermic and hypothermic (pre-exercise 60-min whole-body cooling) conditions during submaximal exercise testing (two 6-min constant-load exercise bouts). Moreover, heart rate, blood lactate content, expiratory volume and ratings of perceived exertion (RPE) were assessed during exercise. RESULTS: Exercise heart rate (-7 ± 6 beats/min) and end-exercise body temperature (-0.9 ± 0.5°C) was significantly lower in hypothermic vs. normothermic conditions in both populations (p < 0.05). In pwMS exercise RPE was lower in hypothermic vs. normothermic condition (p = 0.056). No significantly different MRT was found between normothermic vs. hypothermic conditions in both populations. CONCLUSIONS: Lowering body temperature prior to endurance exercise does not affect muscle oxidative capacity in pwMS, but lowers RPE, thus making it possible to prescribe exercises of greater intensity and/or longer duration. [ABSTRACT FROM AUTHOR]

Background: The impact of multiple sclerosis (MS) on skeletal muscle characteristics, such as muscle fiber cross sectional area (CSA), fiber type proportion, muscle strength and whole muscle mass, remains conflicting. Methods: In this cross sectional study, body composition and muscle strength of the quadriceps were assessed in 34 MS (EDSS: 2.5±0.19) patients and 18 matched healthy controls (HC). Hereafter a muscle biopsy (m.vastus lateralis) was taken. Results: Compared to HC, mean muscle fiber CSA of all fibers, as well as CSA of type I, II and IIa fibers were smaller and muscle strength of the quadriceps was lower in MS patients. Whole body composition was comparable between groups. However, compared to HC, the biopsied leg tended to have a higher fat percentage (p = 0.1) and a lower lean mass (p = 0.06) in MS patients. Conclusion: MS seems to negatively influence skeletal muscle fiber CSA, muscle strength and muscle mass of the lower limbs of mildly affected MS patients. This emphasises the need for rehabilitation programs focusing on muscle preservation of the lower limb. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Background and Purpose. Walking capacity is reduced in subjects with multiple sclerosis (MS). To develop effective exercise interventions to enhance walking capacity, it is important to determine the impact of factors, modifiable by exercise intervention (maximal muscle strength versus muscle oxidative capacity), on walking capacity. The purpose of this pilot study is to discriminate between the impact of maximal muscle strength versus muscle oxidative capacity on walking capacity in subjects with MS. Methods. From 24 patients with MS, muscle oxidative capacity was determined by calculation of exercise-onset oxygen uptake kinetics (mean response time) during submaximal exercise bouts. Maximal muscle strength (isometric knee extension and flexion peak torque) was assessed on dynamometer. All subjects completed a 6-minute walking test. Relationships between walking capacity (as a percentage of normal value) and muscle strength (of knee flexors and extensors) versus muscle oxidative capacity were assessed in multivariate regression analyses. Results. The expanded disability status score (EDSS) showed a significant univariate correlation (r = -0.70, P < 0.004) with walking capacity. In multivariate regression analyses, EDSS and mean response time, but not muscle strength, were independently related to walking capacity (P < 0.05). Conclusions. Walking distance is, next to disability level and not taking neurologic symptoms/deficits into account, primarily related to muscle oxidative capacity in subjects with MS. Additional study is needed to further examine/verify these findings. [ABSTRACT FROM AUTHOR]

Despite many epidemiological studies examining comorbidity in people with multiple sclerosis (pMS), there are conflicting opinions on whether pMS are at more or less risk of cardiovascular disease (CVD) and the metabolic syndrome compared with the general population. As pMS can now expect longer survival, this as an important question both at an individual and public health level. This study aimed to systematically review the literature linking MS to CVD risks and to the risk factors constituting the metabolic syndrome. This systematic review is based on a comprehensive literature search of six databases (Swemed+, Pubmed, Embase, Cochrane, PEDro and CINAHL). In total 34 studies were identified. Despite the high number of identified papers, only limited and inconsistent data exist on the risk factors of the metabolic syndrome and MS. Overall, the data suggest an increased CVD risk in pMS. From the existing studies it is not clear whether the increased risk of CVD is related to an increased risk of obesity or changes in body composition, hypertension, dyslipidemia or type II diabetes in pMS, indicating the need for future research in the field, if we are to advise pMS adequately in avoiding preventable comorbidity. [ABSTRACT FROM PUBLISHER]

OBJECTIVE: To explore the etiology of exercise intolerance in patients with MS, it is analyzed whether a disturbed cardiac autonomic control could be observed during exercise testing in patients with MS, and is related to exercise tolerance. PATIENTS AND METHOD: From 26 MS patients and 15 healthy subjects, exercise-onset (first 20 and 60 seconds) and -offset (1-minute recovery) HR change was determined during a 6-minute constant-load exercise bout on bike. Blood lactate, HR, oxygen uptake, expiratory volume and perceived exertion were assessed during exercise, and compared between groups. In 15 MS patients, a 6-min walking test was executed. RESULT: Twenty-second exercise-onset HR increase was significantly smaller in MS patients (14 ± 7 bts/min) vs. healthy subjects (20 ± 8 bts/min, p < 0.05), and independently related to MS and age in total group (p < 0.05). Sixty-second exercise-onset and -offset HR changes were not different between groups, nor independently related to MS presence (p > 0.05). A significant correlation was found between 20-second exercise-onset HR increase and walking capacity in MS patients (r = 0.64, p < 0.01). CONCLUSION: In MS patients, the early increase in heart rate during endurance exercise is significantly slowed, indicating a disturbed cardiac autonomic control, and is related to exercise tolerance. [ABSTRACT FROM AUTHOR]

Over the past two decades, significant advances have been made in the field of regenerative medicine. However, despite being of the utmost clinical urgency, there remains a paucity of therapeutic strategies for conditions with substantial neurodegeneration such as (progressive) multiple sclerosis (MS), spinal cord injury (SCI), Parkinson's disease (PD) and Alzheimer's disease (AD). Different cell types, such as mesenchymal stromal cells (MSC), neuronal stem cells (NSC), olfactory ensheathing cells (OEC), neurons and a variety of others, already demonstrated safety and regenerative or neuroprotective properties in the central nervous system during the preclinical phase. As a result of these promising findings, in recent years, these necessary types of cell therapies have been intensively tested in clinical trials to establish whether these results could be confirmed in patients. However, extensive research is still needed regarding elucidating the exact mechanism of action, possible immune rejection, functionality and survival of the administered cells, dose, frequency and administration route. To summarize the current state of knowledge, we conducted a systematic review with meta-analysis. A total of 27,043 records were reviewed by two independent assessors and 71 records were included in the final quantitative analysis. These results show that the overall frequency of serious adverse events was low: 0.03 (95% CI: 0.01–0.08). In addition, several trials in MS and SCI reported efficacy data, demonstrating some promising results on clinical outcomes. All randomized controlled studies were at a low risk of bias due to appropriate blinding of the treatment, including assessors and patients. In conclusion, cell-based therapies in neurodegenerative disease are safe and feasible while showing promising clinical improvements. Nevertheless, given their high heterogeneity, the results require a cautious approach. We advocate for the harmonization of study protocols of trials investigating cell-based therapies in neurodegenerative diseases, adverse event reporting and investigation of clinical outcomes. [ABSTRACT FROM AUTHOR]

Cell-based therapies are gaining momentum as promising treatments for rare neurological autoimmune diseases, including neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein antibody-associated disease. The development of targeted cell therapies is hampered by the lack of adequate animal models that mirror the human disease. Most cell-based treatments, including HSCT, CAR-T cell, tolerogenic dendritic cell and mesenchymal stem cell treatment have entered early stage clinical trials or have been used as rescue treatment in treatment-refractory cases. The development of antigen-specific cell-based immunotherapies for autoimmune diseases is slowed down by the rarity of the diseases, the lack of surrogate outcomes and biomarkers that are able to predict long-term outcomes and/or therapy effectiveness as well as challenges in the manufacturing of cellular products. These challenges are likely to be overcome by future research. [ABSTRACT FROM AUTHOR]

Currently, there is still no cure for multiple sclerosis (MS), which is an autoimmune and neurodegenerative disease of the central nervous system. Treatment options predominantly consist of drugs that affect adaptive immunity and lead to a reduction of the inflammatory disease activity. A broad range of possible cell-based therapeutic options are being explored in the treatment of autoimmune diseases, including MS. This review aims to provide an overview of recent and future advances in the development of cell-based treatment options for the induction of tolerance in MS. Here, we will focus on haematopoietic stem cells, mesenchymal stromal cells, regulatory T cells and dendritic cells. We will also focus on less familiar cell types that are used in cell therapy, including B cells, natural killer cells and peripheral blood mononuclear cells. We will address key issues regarding the depicted therapies and highlight the major challenges that lie ahead to successfully reverse autoimmune diseases, such as MS, while minimising the side effects. Although cell-based therapies are well known and used in the treatment of several cancers, cell-based treatment options hold promise for the future treatment of autoimmune diseases in general, and MS in particular. [ABSTRACT FROM AUTHOR]

Genetic engineering of regulatory T cells (Tregs) presents a promising avenue for advancing immunotherapeutic strategies, particularly in autoimmune diseases and transplantation. This study explores the modification of Tregs via mRNA electroporation, investigating the influence of T-cell activation status on transfection efficiency, phenotype, and functionality. For this CD45RA + Tregs were isolated, expanded, and modified to overexpress brain-derived neurotrophic factor (BDNF). Kinetics of BDNF expression and secretion were explored. Treg activation state was assessed by checking the expression of activation markers CD69, CD71, and CD137. Our findings show that only activated Tregs secrete BDNF post-genetic engineering, even though both activated and resting Tregs express BDNF intracellularly. Notably, the mTOR pathway and CD137 are implicated in the regulation of protein secretion in activated Tregs, indicating a complex interplay of signalling pathways. This study contributes to understanding the mechanisms governing protein expression and secretion in engineered Tregs, offering insights for optimizing cell-based therapies and advancing immune regulation strategies., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)

Introduction: Based on the advances in the treatment of multiple sclerosis (MS), currently available disease-modifying treatments (DMT) have positively influenced the disease course of MS. However, the efficacy of DMT is highly variable and increasing treatment efficacy comes with a more severe risk profile. Hence, the unmet need for safer and more selective treatments remains. Specifically restoring immune tolerance towards myelin antigens may provide an attractive alternative. In this respect, antigen-specific tolerisation with autologous tolerogenic dendritic cells (tolDC) is a promising approach., Methods and Analysis: Here, we will evaluate the clinical use of tolDC in a well-defined population of MS patients in two phase I clinical trials. In doing so, we aim to compare two ways of tolDC administration, namely intradermal and intranodal. The cells will be injected at consecutive intervals in three cohorts receiving incremental doses of tolDC, according to a best-of-five design. The primary objective is to assess the safety and feasibility of tolDC administration. For safety, the number of adverse events including MRI and clinical outcomes will be assessed. For feasibility, successful production of tolDC will be determined. Secondary endpoints include clinical and MRI outcome measures. The patients' immune profile will be assessed to find presumptive evidence for a tolerogenic effect in vivo., Ethics and Dissemination: Ethics approval was obtained for the two phase I clinical trials. The results of the trials will be disseminated in a peer-reviewed journal, at scientific conferences and to patient associations., Trial Registration Numbers: NCT02618902 and NCT02903537; EudraCT numbers: 2015-002975-16 and 2015-003541-26., Competing Interests: Competing interests: CCG received speaker honoraria and travel expenses for attending meeting from Genzyme, Novartis Pharma GmbH, and Bayer Health Care. Her work is funded by the German Ministry for Education and Research (BMBF; 01GI1603A) and the German Research Foundation (DFG; GR3946/3-1 and SFB128 A09). HW receives honoraria for acting as a member of Scientific Advisory Boards and as consultant for Biogen, Evgen, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma AG, Sanofi-Genzyme, as well as speaker honoraria and travel support from Alexion, Biogen, Cognomed, F. Hoffmann-La Roche Ltd., Gemeinnützige Hertie-Stiftung, Merck Serono, Novartis, Roche Pharma AG, Sanofi-Genzyme, TEVA, and WebMD Global. Prof. Wiendl is acting as a paid consultant for Abbvie, Actelion, Biogen, IGES, Novartis, Roche, Sanofi-Genzyme, and the Swiss Multiple Sclerosis Society. His research is funded by the German Ministry for Education and Research (BMBF; 01FI1601E, 01GI1603A, and O1GI1603D), Deutsche Forschungsgesellschaft (DFG; SFB128 A09, A10, Z02, V and SFB1009 A03), Else Kröner Fresenius Foundation, Fresenius Foundation, Hertie Foundation, NRW Ministry of Education and Research, Interdisciplinary Center for Clinical Studies (IZKF) Muenster and RE Children’s Foundation, Biogen GmbH, GlaxoSmithKline GmbH, Roche Pharma AG, Sanofi-Genzyme. The institution of BW receives honoraria for acting as a member of Scientific Advisory Boards for Biogen, Merck Serono, Roche, Sanofi-Genzyme, Novartis and speaker honoraria and travel support from Biogen, Merck Serono, Roche, Sanofi-Genzyme, Novartis, TEVA. CRT receives honoraria for acting as a member of Scientific Advisory Boards for Biogen, and Merck Serono, and speaker honoraria or travel support from Biogen, Merck Serono, Roche, Sanofi-Genzyme and Novartis. SPR receives speaker honoraria or travel support from Biogen, Merck Serono, Roche, Sanofi-Genzyme and Novartis. PP is a medical advisory board member of Icometrix NV. The other authors report no conflict of interest., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)