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Background. Low physical activity levels in persons with multiple sclerosis (MS) may reduce skeletal muscle oxidative capacity. Rehabilitation strategies might be altered by a measure of capacity that did not require invasive techniques or maximal exercise testing. For this purpose, we measured exercise onset and offset oxygen uptake (Vo(2)) kinetics during endurance exercise. Objective. This study compared exercise-onset and -offset Vo(2) kinetics in mildly affected persons with MS with healthy matched participants. Methods. From 38 MS patients who had a mean Expanded Disability Status Scale of 3.1 and 16 healthy participants, exercise-onset and -offset Vo(2) kinetics (mean response time [MRT]) were determined during two 6-minute submaximal bouts of exercise separated by a 6-minute recovery interval. Blood lactate, heart rate, expiratory volume, and Borg ratings of perceived exertion were assessed during exercise and compared between groups. Relationships between clinical characteristics and MRT were assessed. Results. During exercise, blood lactate, heart rate, and expiratory volume did not differ between groups (P > .05), but exercise-onset MRT was significantly slower in MS versus healthy participants (P = .007). Exercise-onset MRT was independently related to having MS (P = .02). Exercise-offset MRT was not different between groups or was independently related to having MS (P > .05). No independent relationships between clinical characteristics of MS and exercise-onset or -offset MRT were found. Conclusions. Exercise-onset Vo(2) kinetics during submaximal endurance exercise are significantly slowed in mildly disabled persons with MS, suggesting low skeletal muscle oxidative capacity. Using mean response time testing, rehabilitation interventions for this reduction in exercise capacity can be assessed and targeted.

Multiple Sclerosis patients sometimes experience their forward swinging feet to catch the floor unintentionally. Minimally impaired Multiple Sclerosis patients, during terminal-swing phases of gait, may even produce shuffling sounds, by the lateral soles of their feet over the ground. To prevent tripping, such patients should train their medial hamstring muscles. Renewed interest in gait and balance in Multiple Sclerosis emerges, as the 1st International Symposium on Gait and Balance in Multiple Sclerosis testifies (International Journal of MS Care, 2011). However, little attention is given to the swing phase of gait in early Multiple Sclerosis patients. Remarkably, various early diagnosed Multiple Sclerosis patients produce audible shuffling sounds, caused by the lateral soles of their shod feet over the ground, during the terminal-swing phase of gait. The common cause seems to be foot-drop including foot-inversion. Foot-inversion is defined as turning the sole of the foot inward, while foot-eversion is turning the sole outward. Recent quantitative data on exercise therapies of ankle weakness patients clearly show that normal foot eversion goes together with simultaneous shank internal rotation. From a functional-anatomical point of view, normal internal shank rotation during knee flexion is effectuated by the medial hamstring muscles. Most authors therefore agree on training Multiple Sclerosis patients´ hamstrings. Strength training of hamstring muscles appears to have positive effects on muscular function and gait speed in Multiple Sclerosis patients. We presume that the abnormal lateral foot shuffling in swing may easily lead to the much-dreaded tripping, stumbling and falling with their far-reaching consequences. This should be avoided as much as possible. University of Hasselt Scientific Contract Research 2012 -2013, Project : Foot inversion and eversion movements in stance and swing - some comparative-anatomical and functional morphological aspects (R-3500)

Given the increase in global mean prevalence of MS and other autoimmune disease, and the unmet medical need, the quest for new disease-specific treatments continues. In the last decennia, the regulatory mechanisms of the immune system were exploited therapeutically to reshape immune responses and induce durable immune tolerance. Also, adaptive regulatory T cell (Treg) therapy has found its way to the clinic with dozens of clinical trials ongoing and finished. To date, researchers seek to augment clinical efficacy by using a broad range of molecular engineering methods with the first clinical trials using engineered Tregs ongoing. The general aim of this thesis was to develop a clinically safe vaccine for the treatment of MS, based on Tregs specifically targeting cells involved in the onset and progression of the disease. In addition, we provide an alternative for currently used engineering methods, which have shown pre-clinical efficacy and thus clinical potential, but also possess multiple safety concerns. In doing so, we aimed to advance the field of Treg therapy by providing in vitro proof of TCR-encoding mRNA-transfected Tregs and we are convinced that the work presented in these thesis will play its part in the road to long-lasting tolerance in MS and other autoimmune diseases.

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 α-/β-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 α-/β-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 α-/β-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. This work was supported by the Hasselt University and Maastricht University and Research Foundation – Flanders (FWO) [grant number KAN 1507217N]

Uit vorige studies is gebleken dat MS patiënten heel wat intramusculaire veranderingen ondergaan die deels het verlies in spierkracht en vermoeidheid bij deze patiënten kunnen verklaren. Mogelijks zijn verlaagde carnosineconcentraties één van die spierveranderingen in MS, maar dit is nooit effectief onderzocht geweest. Indien dit het geval zou zijn, moet er naar middelen gezocht worden om carnosine in de spieren te verhogen om zo eventueel revalidatie-uitkomsten te verbeteren. Wij onderzoeken daarom in een dierenmodel voor MS en MS patiënten zelf of de spiercarnosine concentraties verlaagd zijn ten opzichte van gezonde controlegroepen. Daarnaast gaan wij na of training dit zou kunnen verhogen.

In this paper, the effect of high-intensity interval plus resistance training (HIITR) on cardiovascular risk factors was studied through a quasi-experimental study. Outcome measures are: endurance capacity, body composition, physical activity level, isometric muscle strength, oral glucose tolerance, blood lipids and lipoprotein - cholesterol.

Despite frequent muscle strength or muscle oxidative capacity (based on exercise-onset oxygen uptake [VO2] kinetics) assessments in patients with multiple sclerosis, the impact of time of day on these parameters is often not taken into account. Based on observations in healthy subjects, it remains to be studied whether muscle strength, and/or exercise-onset VO2 kinetics, varies between the morning and the afternoon in patients with multiple sclerosis. In this prospective observational pilot study, walking capacity, exercise-onset VO2 kinetics, isometric knee extension/flexion strength (dynamometry), and self-reported fatigue were measured in 11 patients with multiple sclerosis (age, 51.8 +/- 9.3 yrs; body mass index, 24.7 +/- 5.1 kg/m(2); Expanded Disability Status Scale, 3.5 +/- 1.4; 3 men) in the morning and 5 hrs later (afternoon). In the afternoon, self-reported fatigue (1.9 +/- 0.9 cm) and muscle strength (knee extension peak torque at 45 degrees, 84 +/- 26 Nm) were significantly different (P < 0.05), than in the morning (self-reported fatigue, 1.2 +/- 0.9 cm; knee extension peak torque at 45 degrees, 93 +/- 32 Nm), but walking capacity and exercise-onset VO2 kinetics were similar at these two time points (P > 0.05). Consistent with observations in healthy subjects, muscle strength varies between the morning and the afternoon in patients with multiple sclerosis, under the conditions of the present study. These findings suggest that muscle strength assessments should be conducted at similar or nearly similar times of the day to minimize diurnal variation in these measures and hence insure correct interpretation.

Uit vorige studies is gebleken dat MS patiënten heel wat intramusculaire veranderingen ondergaan die deels het verlies in spierkracht en vermoeidheid bij deze patiënten kunnen verklaren. Mogelijks is een verlaagde carnosineconcentratie één van die spierveranderingen in MS, maar dit is nooit effectief onderzocht geweest. Indien dit het geval zou zijn, moet er naar middelen gezocht worden om carnosine in de spieren te verhogen om zo eventueel revalidatie-uitkomsten te verbeteren. Wij onderzoeken daarom in een dierenmodel voor MS en MS patiënten zelf of de spiercarnosine concentraties verlaagd zijn ten opzichte van gezonde controlegroepen . Daarnaast gaan wij na of training dit kan verhogen.

Multiple sclerosis (MS) is characterized by complex heterogeneous symptoms, which often leads to a more sedentary lifestyle. This lifestyle increases the likelihood to develop secondary health problems, like cardiometabolic risk (CMR) profile. However, in other population these secondary health problems can be, partly, reversed by exercise therapy. We hypothesized that MS affects the CMR profile, but the outcome can be reversed following exercise therapy. Persons with MS and matched healthy controls (HC) were screened to assess their CMR profile, as well as left ventricular (LV) function and exercise tolerance. Based on their CMR profile, MS patients were selected for the intervention study and were randomized to an exercise group or a non-exercise group. Baseline screening revealed that MS patients have a higher CMR profile compared to HC, due to IGT and elevated blood pressure. Furthermore, we observed an increased prevalence of LV dysfunction in MS patients and lowered endurance capacity. However, no significant changes were observed in CMR profile, or LV function after the 12 weeks of training in the exercise group, compared to baseline. In contrast, exercise tolerance in the exercise group did change. MS seems to negatively influence the CMR profile, LV function, as well as exercise tolerance. However, the increased CMR risk could not be improved following 12 weeks of exercise training.

Objectives Multiple sclerosis (MS) is a highly investigated neurologic disorder, creating dysfunction and disability. The demyelination of the central nervous system can cause disturbances in the autonomic regulation. The existence of cardiovascular autonomic dysfunction (CAD) within this population remains uncertain. The aim of this study was to examine the existence of CAD in the MS population, compared to the healthy population. Methods Seventy-five participants were included in this screening study, including 51 MS patients and 24 age- and sex matched healthy controls. The participants were subjected to five different autonomic tests: sustained handgrip test, valsalva maneuver, deep breathing test, cold pressure test and passive tilt test. Heart rate and/or blood pressure responses were continuously measured. Results There were no differences in age and sex between the MS and the control group. There was no significant difference in the prevalence of CAD in the MS group (38.78%) and the control group (30.43%). During the deep breathing test the variation in heart rate was significantly lower in MS patients compared to the healthy controls. Other autonomic tests failed to show a significant difference between both groups. Regarding the MS group, small but significant correlations were discovered between the EDSS/disease duration and the results from the deep breathing test. Conclusion The results of this study did not indicate CAD in MS in comparison to the healthy population.

This literature study fits in the research domain of cardiorespiratory and internal diseases as well as the neurological subdomain of the rehabilitation sciences and physiotherapy department of Hasselt University and is constructed according to the central format. The effect of high-intensity interval training (HIIT) on biomarkers of mitochondrial biogenesis and mitochondrial density in skeletal muscles of patients with multiple sclerosis (pwMS) was studied through a literature review. Outcome measures are: peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1'), p38 mitogen-activated protein kinase (p38-MAPK), adenosine monophosphate-activated protein kinase (AMPK), adenosine triphosphate (ATP), cytochrome c oxidase (COX) and citrate synthase (CS). HIIT was the intervention of choice because of the small effect size of low to moderate intensity exercise. Here, higher intensity exercise might improve therapy outcomes, due to the major advantages of intense bursts of activity interspersed with fixed periods of less-intense activity, or even complete rest. Exercise duration of HIIT is short in comparison with endurance exercise. This makes it an interesting exercise modality for pwMS who often have a reduced exercise capacity. In the second part of this study, a research protocol is described.

Objective: The aim of this study was to investigate the effect of high-intensity interval training (HIIT) on the glucose metabolism of MS patients. Methods: Baseline differences in body composition and glucose metabolism between MS patients (MS) (n=29) and healthy controls (HC) (n=26) were determined by OGTT and DEXA-scan. Subsequently, the MS group was separated into an intervention group (EX) (n=16) which completed a 12 week HIIT protocol, and a sedentary control group (SED) (n=13). Glucose metabolism and body composition were investigated in both groups at baseline and after twelve weeks. Results: Baseline analysis showed significantly increased fasting serum insulin concentrations (p=0.0109) of the MS group compared to the HC group. Surprisingly, glucose total area under the curve (tAUC) (p=0.0244) of SED was significantly decreased after twelve weeks. Within-group analysis of the EX group showed a significant decrease in fasting serum insulin (p=0.0495) and HOMA-IR (p=0.0245) concentrations.

The prevalence of impaired glucose tolerance is increased in individuals with Multiple Sclerosis (MS). Similar to other populations, it has been suggested that higher intensity rehabilitation/training programs could improve glucose tolerance in MS. However, because the use of a high intensity program was never investigated before in this population, it seems warranted to first explore this in an animal (rat) model for MS, notably experimental autoimmune encephalomyelitis (EAE). This thesis aims to investigate the impact of high intensity exercise on glucose tolerance (GT) and insulin in EAE rats. EAE nor exercise were able to affect glucose tolerance. However, glucose tAUC was increased after hindquarter paralysis.

Background: Recent research reported a higher prevalence of impaired glucose tolerance (IGT) in MS patients than in healthy people. The influence of high intensity exercise on IGT in MS was never investigated before. Objective: To investigate the effect of high intensity aerobic interval (HIIT) or continuous endurance (CT) training, both in combination with resistance training, on glucose tolerance muscle strength and body composition. Methods: 34 subjects were randomly assigned to a control group (n=11), to a group who received a combined cardiovascular and resistance training program (n=11) or to a group who received a combined high-intensity interval training (HIIT) and resistance training program (n=12). At baseline and after 12 weeks, glucose tolerance was measured using an Oral Glucose Tolerance Test, muscle strength was measured using an isokinetic dynamometer and the DEXA was used to measure body composition. Results: A significant decrease of glucose concentration was seen in both groups. Furthermore, muscle strength and body composition improved in both exercise groups, whereas all outcome measures remained stable in the sedentary control group. Conclusion: Twelve weeks of high intensity aerobic exercise in combination with resistance training was safe and well tolerated and induced changes in glucose tolerance in MS patients.

Background Patients with MS (pwMS) often experience resting ventilatory anomalies. Ventilatory function during exercise and impact of long-term training intervention remains however uncertain. Aim To examine the ventilatory function during exercise and impact of a 6-month training intervention in pwMS. Design Combination of a cross-sectional (part 1) and randomized controlled trial (part 2). Setting University rehabilitation facility. Population Caucasian patients with MS and healthy controls. Methods In part 1, the ventilatory function during submaximal endurance exercise was compared between pwMS (n=37) and healthy participants (n=15). In part 2, pwMS were then randomly assigned to a 6-month training intervention (n=16) or usual care (n=11). Following training intervention, ventilatory function during exercise was re-evaluated. Results Despite comparable relative exercise testing intensities between groups in part 1, significantly elevated steady-state exercise dead space/tidal volume ratio, O2 uptake and CO2 output equivalent, end-tidal O2 pressure, ratings of perceived exertion and lowered end-tidal CO2 pressure and O2 pulse was observed in pwMS (p0.05). Conclusion Patients with MS experience a ventilatory dysfunction during endurance exercise, which is related to worse exercise tolerance. This ventilatory anomaly remains present after long-term training intervention. Clinical rehabilitation impact Patients with MS experience ventilatory dysfunction during exercise. This dysfunction is related to exercise tolerance and ratings of perceived exertion. Long-term exercise training did not remediate this ventilatory dysfunction. The systematic examination of the pulmonary/cardiovascular system at rest and during exercise is recommended in MS.