Endurance training in MS: short-term immune responses and their relation to cardiorespiratory fitness, health-related quality of life, and fatigue

The influences of exercise on cytokine response, health-related quality of life (HR-QoL), and fatigue are important aspects of MS rehabilitation. Physical exercises performed within these programs are often practiced in water, but the effects of immersion have not been investigated. To investigate the influences of short-term immune responses and cardiorespiratory fitness on HR-QoL and fatigue during 3 weeks endurance training conducted on a cycle-ergometer or an aquatic-bike. Randomized controlled clinical trial in 60 MS patients. HR-QoL, fatigue, cardiorespiratory fitness, and short-term immune changes (serum concentrations in response to cardiopulmonary exercise test) of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), interleukin-6, and the soluble receptor of IL-6 (sIL-6R) were determined at the beginning and end of 3 weeks of training intervention. Subjects performed daily 30 min training at 60 % of their VO2peak. SF-36 total (p = 0.031), physical (p = 0.004), and mental health (p = 0.057) scores show time effects within both groups. Between-group effects were shown for FSMC total (p = 0.040) and motor function score (p = 0.041). MFIS physical fatigue showed time effects (p = 0.008) for both groups. Linear regression models showed relationships between short-term immune responses and cardiorespiratory fitness with HR-QoL and fatigue after the intervention. This study indicates beneficial effects of endurance training independent of the training setting. Short-term immune adaptations and cardiorespiratory fitness have the potential to influence HR-QoL and fatigue in persons with MS. The specific immune responses of immersion to exercise need further clarification.     

Factors limiting maximal oxygen uptake in exertional monoparesis

Strength and maximal oxygen uptake (VO2max) for each leg were compared in a trained multiple sclerosis (MS) patient with exertional left monoparesis. Left quadriceps strength and left leg VO2max were 22% and 30% lower, respectively, compared to the right (control) leg. Because the same O2 delivery system served each leg during exercise, VO2max of the paretic leg was not limited by cardiorespiratory factors but rather by strength and/or muscle oxidative capacity. However, training with monoparesis likely enhanced O2 extraction and aerobic work capacity of the right leg.     

Aerobic capacity in early paraplegia: implications for rehabilitation

Both strength (ability to develop tension) and endurance (aerobic capacity as measured by VO2 max) contribute to overall functional capacity. In the rehabilitation of individuals with major neuromuscular deficits such as paraplegia, primary emphasis is generally placed on strength training to develop functional independence. However, endurance training may also be important. To clarify the influence of paraplegia on the VO2, we studied 10 paraplegics between 2 to 12 weeks after injury to determine whether or not a deficit in arm VO2 max was present before the inception of a conventional rehabilitation programme, and whether it persisted in three subjects after its completion. Cardiorespiratory responses to progressive multi-stage arm ergometry were measured using standard open circuit calorimetry. Ten paraplegic subjects demonstrated a low VO2 max compared to control subjects. This deficit persisted when selected subjects (n = 3) were tested after completion of a conventional rehabilitation programme which emphasised strengthening exercises. Further research is needed to study the effects of complementary endurance training on the aerobic capacity as measured by VO2 max, and to assess their value in the rehabilitation process.     

Comparison of the influence of different rehabilitation programmes on clinical, spirometric and spiroergometric parameters in patients with multiple sclerosis

PURPOSE: The aim of this study was to compare the effect of four different programmes on spiroergometric, spirometric and clinical parameters in multiple sclerosis (MS) patients. METHODS: One hundred and twelve MS patients were divided into four groups. The first group underwent neurophysiologically based physiotherapy, the second aerobic training, the third combined therapy (neurophysiologically based physiotherapy and aerobic training) and the fourth did not change any habits. Seventeen patients did not finish the study. Patients were examined on impairment (Expanded Disability Status Scale), disability (Barthel Index), handicap (Environment Status Scale), quality of life (Multiple Sclerosis Quality of Life), fatigue (Modified Fatigue Impact Scale), depression (Beck Depression Inventory Score), respiratory function (spirometric parameters on spirometry) and physical fitness (spiroergometric parameters on a bicycle ergometer). RESULTS: The patients who participated in one of our training programmes showed a significant improvement of the examined parameters in comparison to those who did not change their present habits. Each of the four training programmes had a different impact on the parameters, which means that each of them had a different effect. The neurophysiologically based physiotherapy had the greatest impact on impairment, and the aerobic training on spirometric and spiroergometric parameters. All methods (the neurophysiologically based physiotherapy, the aerobic training and the combined programme) had an impact on fatigue.     

Comparing aerobic with nonaerobic forms of exercise in the treatment of clinical depression: a randomized trial

We compared aerobic with nonaerobic forms of exercise in the treatment of clinical depression. Ninety-nine inpatients, who met the DMS-III-R criteria for major depression, dysthymic disorder, or depressive disorder not otherwise specified (NOS), took part in the study. They were randomly assigned to two different physical training conditions, aerobic and nonaerobic. In both conditions, one hour of training was performed three times a week for a period of 8 weeks. There was a significant increase in maximum oxygen uptake (VO2 max) in the aerobic group; there was no change in the nonaerobic group regarding this variable. Depression scores in both groups were significantly reduced during the study, but there was no significant difference between the groups. The correlation between increase in physical fitness and reduction in depression scores was low. The study indicates that the antidepressive effects associated with exercises are not restricted to aerobic forms of training.     

Immune-endocrine host response to endotoxin in major depression

OBJECTIVE: An impaired hypothalamic-pituitary-adrenocortical (HPA) function is a well-established finding in major depression (MD), but it is still unclear how this dysfunction affects immune responses in this disorder. METHOD: To further examine the relationship between immune and endocrine responses in MD, 0.4ng/kg body weight endotoxin [LPS] or 100mug hCRH were sequentially applied to 12 patients with MD and to 12 age- and gender-matched healthy controls after pre-treatment with 1.5mg dexamethasone (DEX). Immune (TNF-alpha, IL-6, rectal temperature) and endocrine (ACTH, cortisol) parameters were examined as area under the curve (AUC) levels. RESULTS: After pre-treatment with DEX, LPS evoked an immune response in all participants of the study with most immune parameters significantly related to the endotoxin challenge. However, only a marked immune response resulted in an additional endocrine reaction. Subsequently, the quantitative extent of the endocrine reaction was related to the extent of the immune response after DEX/LPS challenge. Pre-LPS AUC levels of cortisol, ACTH and post-LPS levels of IL-6 as well as the post-CRH AUC levels of cortisol and ACTH were related to the depressive symptomatology as measured by the Beck depression inventory (BDI). In depressive patients who showed increased cortisol plasma levels before LPS, the later increase in IL-6 was reduced. CONCLUSIONS: The challenge with DEX/LPS did not reveal major impairments of evoked immune functions in MD. Only the endocrine parameters and the IL-6 response were related to the depressive symptomatology, suggesting a limited interaction between immune and endocrine dysfunctions in MD.     

Endocrine and cytokine responses to acute psychological stress in multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system. An impaired hypothalamopituitary axis and stress reactivity have extensively been discussed without convincing experimental evidence. We choose a standardized acute psychological stressor to determine whether MS patients show altered endocrine and immune responses to stress. In 35 relapsing-remitting MS patients we found elevated baseline levels for catecholamines, prolactin, and IL-6 compared to 15 healthy controls. All neuroendocrine parameters declined during the stress intervention in MS as well as in stress-exposed controls. But only prolactin showed a significantly larger decline in stressed MS patients versus controls. During exposure to the stress we found no significant changes in serum levels of IL-6, IL-6 receptor, or TNF-alpha in either MS patients or controls after stimulation of a whole blood culture. An altered neural immune signaling in relapsing-remitting MS patients during acute experimental stress could not be proven for the parameters analyzed.     

Impact of aerobic training on fitness and quality of life in multiple sclerosis

Fifty-four multiple sclerosis (MS) patients were randomly assigned to exercise (EX) or nonexercise (NEX) groups. Before and after 15 weeks of aerobic training, aspects of fitness including maximal aerobic capacity (Vo2max), isometric strength, body composition, and blood lipids were measured. Daily activities, mood, fatigue, and disease status were measured by the Profile of Mood States (POMS), Sickness Impact Profile (SIP), Fatigue Severity Scale (FSS), and neurological examination. Training consisted of 3 × 40-minute sessions per week of combined arm and leg ergometry. Expanded Disability Status Scale (EDSS) scores were unchanged, except for improved bowel and bladder function in the EX group. Compared with baseline, the EX group demonstrated significant increases in Vo2max, upper and lower extremity strength, and significant decreases in skinfolds, triglyceride, and very-low-density lipoprotein (VLDL). For the EX group, POMS depression and anger scores were significantly reduced at weeks 5 and 10, and fatigue was reduced at week 10. The EX group improved significantly on all components of the physical dimension of the SIP and showed significant improvements for social interaction, emotional behavior, home management, total SIP score, and recreation and past times. No changes were observed for EX or NEX groups on the FSS. Exercise training resulted in improved fitness and had a positive impact on factors related to quality of life.     

Aerobic Training Efficacy in Inflammation,Neurotrophins, and Function in Chronic Stroke Persons: A Randomized Controlled Trial Protocol

Background: Neuroinflammation is an important part of stroke pathophysiology and has both detrimental and beneficial effects after stroke. Besides that the enhancement of neurotrophins seems to be related to improvements in stroke recovery. Evidences suggest that exercise plays a role in modulating anti-inflammatory and neurotrophic effects. However, little is known about its impact in stroke survivors, mainly in chronic stroke. The purpose of this study is to investigate the efficacy of moderate-intensity treadmill exercise in changing inflammatory mediators, interleukin-6 (IL-6), soluble tumor necrosis factor receptors I and II (sTNFRI, sTNFRII), interleukin-10 (IL-10), and brain-derived neurotrophic factor (BDNF) levels in chronic stroke patients. The secondary objective is to investigate the effects of training in improve mobility and exercise capacity. Methods: This is a randomized controlled trial. Chronic stroke patients will be randomized to an experimental or control group, and will receive group interventions three times per week, over 12 weeks. The experimental group will receive moderate-intensity (60%-80% of maximum heart rate reserve) treadmill exercise. Control group will perform walking training on the ground (<40% of maximum heart rate reserve). Primary outcomes include IL-6, sTNFRI, sTNFRII, IL-10, and BDNF levels. Secondary outcomes include mobility and exercise capacity. Outcomes will be measured at baseline, postintervention, and at the 4-week follow-up. Discussion: The findings of this trial have the potential to provide important insights regarding the effects of an aerobic physical program in the inflammatory process and in the neuronal plasticity in stroke persons and its impact on mobility and exercise capacity.     

Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis

Multiple sclerosis (MS) patients of an inpatient rehabilitation program have been randomly assigned to an exercise training (MS-ET) or nontraining group (MS-NI). Before and after 4 weeks of aerobic exercise training, a graded maximal exercise test with measurement of gas exchange and a lung function test was administered to all 26 patients fulfilling the inclusion criteria. Activity level, fatigue and health perception were measured by means of questionnaires. Twenty-six healthy persons served as control group and were matched in respect of age, gender and activity level. Training intervention consisted of 5x30 min sessions per week of bicycle exercise with individualised intensity. Compared with baseline, the MS training group demonstrated a significant rightward placement of the aerobic threshold (AT) (VO2+13%; work rate [WR])+11%), an improvement of health perception (vitality+46%; social interaction+36%), an increase of activity level (+17%) and a tendency to less fatigue. No changes were observed for the MS-NI group and the control groups. Maximal aerobic capacity and lung function were not changed by either training or nontraining in all four groups. Overall compliance to the training program was quite low (65%), whereas incidence of symptom exacerbation by physical activity has been lower than expected (6%).     

The HPA axis response to stress in women: effects of aging and fitness

This study tested the hypotheses that aging is associated with greater hypothalamic-pituitary-adrenal (HPA) axis reactivity to psychological stress, and whether aerobic fitness is associated with a lower HPA axis response to psychological stress. Three groups, consisting of young-unfit women (27.9+/-2.5 yr, n=10), older-unfit women (66.3+/-1.4 yr, n=14), and older-fit women (66.6+/-2.0 yr, n=12), underwent the Matt Stress Reactivity Protocol (MSRP). The MSRP is a stress test battery that combines mental challenges, a physical challenge, and a psychosocial stressor. Definition of fitness was based on maximal oxygen consumption (VO(2max)) where unfit was defined as having VO(2max)average for the respective age group. The MSRP elicited increases in heart rate, blood pressure, ACTH, and cortisol (P<0.001). The older-unfit women had significantly greater cortisol responses to the challenge than both the young-unfit and the older-fit women (P<0.05), who did not differ from each other. ACTH levels were significantly higher in the older-unfit women at baseline and throughout the trial, compared to both young-unfit and the older-fit (P<0.01). The ACTH response was not different between any of the groups. The young-unfit women had greater heart rate responses than the older-unfit (P<0.01), while the latter had greater systolic blood pressure responses (P<0.01). There were no significant differences between the older-unfit and older-fit in terms of heart rate or blood pressure responses. Our result shows that among unfit women, aging is associated with greater HPA axis reactivity to psychological stress, and that higher aerobic fitness among older women can attenuate these age-related changes as indicated by a blunted cortisol response to psychological stress. These findings suggest that exercise training may be an effective way of modifying some of the neuroendocrine changes associated with aging.     

Effects of heart-rate feedback on estimated cardiovascular fitness in patients with panic disorder

Psychological parameters that are believed to affect estimations of cardiovascular fitness were examined in patients with panic disorder and nonclinical controls. Fifty-four participants [panic disorder patients (n = 27) and age- and sex-matched nonclinical controls (n = 27)] completed a cycle ergometer test and were compared on the basis of estimated VO2 max. Participants were randomly assigned to experimental conditions in which they received heart-rate feedback or no feedback during the test. Patients with panic disorder exhibited lower VO2 max and decreased exercise tolerance (i.e., were more likely to discontinue the test) than nonclinical controls. Furthermore, individuals with high anxiety sensitivity (i.e., a fear of autonomic arousal), but not a panic disorder diagnosis per se, achieved significantly lower VO2 max when provided with heart-rate feedback. Moreover, diagnostic status interacted with levels of anxiety sensitivity to predict VO2 max. Patients with panic disorder display poorer cardiovascular fitness after controlling for anxiety and other factors that underestimate performance during fitness testing.     

Interferon-beta regulates cytokines and BDNF: greater effect in relapsing than in progressive multiple sclerosis

The mechanism of action of interferon (IFN)-beta therapy in multiple sclerosis (MS) is only partially known, and its efficacy changes with disease stage. In different forms of MS, we determined how IFN-beta regulates mononuclear cell production of the important anti-inflammatory Th2 cytokine - IL-10, the Th1 cytokine - IFN-gamma, and the brain-derived neurotrophic protein - BDNF. Activated T cells and monocytes from therapy-na?ve patients secreted more IL-10 than healthy controls. During IFN-beta therapy, however, T cells produced less IL-10. In vitro, IFN-beta stimulated IL-10 production by activated T cells, but inhibited IL-10 secretion by activated monocytes, a richer source of IL-10 than T cells. The form of MS also affected cytokine production. IL-10 and BDNF levels in MNC were high during relapsing/remitting (RR) MS, but low in progressive MS. Surprisingly, IFN-beta therapy increased BDNF levels in antidepressant-na?ve patients, but BDNF was lower during concurrent antidepressant drug therapy, suggesting an interaction between MS, depression, and neurodegeneration. IFN-beta in vitro strongly induced IL-10 and IFN-gamma in activated T cells in RRMS, but not in progressive MS, suggesting IFN resistance. IFN-beta effects are specific for disease state and immune subsets, possibly explaining why IFN-beta therapy is most effective in early T cell-regulated RRMS, but less beneficial in progressive MS, where chronic plaques contain few T cells and high numbers of monocytes.     

Investigation of cytokine (tumor necrosis factor-alpha, interleukin-6, interleukin-10) concentrations in the cerebrospinal fluid of female patients with multiple sclerosis and systemic lupus erythematosus.

Humoral immune response seems to play a role in the pathogenesis of multiple sclerosis (MS) and in the central nervous system (CNS) complications of systemic lupus erythematosus (SLE). The aim of the present study was to compare the levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and IL-10 in the cerebrospinal fluid of female patients with several forms of MS (50 patients), and in female patients with several types of CNS complications in SLE (50 patients). Samples were investigated using an enzyme-linked immunosorbent assay technique. Involvement of CNS in SLE patients seems to be characterized with elevated concentrations of all three cytokines in CNS and intrathecal synthesis of IL-6. In MS patients, an intrathecal synthesis of TNF-alpha (relapsing-remitting form) and IL-6 (primary progressive form) were observed. Clinical forms of MS seem to be immunologically heterogeneous. The activation of cytokine network was observed in SLE patients with CNS complications, independent of the pathological process. Similarities between SLE and MS patients with the primary progressive form of the disease were demonstrated concerning the intrathecal synthesis of IL-6. Only MS patients with the relapsing-remitting clinical form showed intrathecal TNF-alpha synthesis.     

Chronic stress in nonelderly caregivers: Psychological, endocrine and immune implications

Objective: This investigation examined whether the immune dysregulation that characterises elderly informal caregivers (e.g., spousal caregivers of dementia patients) extends to a younger caregiver population, specifically spousal carers of patients with multiple sclerosis (MS). Method: MS spousal caregivers (n=41, mean age 43 years, 14 women, 27 men) and noncaregiving controls (n=62, mean age 33 years, 44 women, 18 men) were recruited. Psychological morbidity (i.e., self-reported stress, anxiety and depression), endocrine activity (i.e., salivary cortisol and DHEAs) and immunity (i.e., IgG and HAI responses to influenza vaccination and IFN-γ and IL-4 levels) were assessed. Results and Conclusions: MS caregivers and noncaregivers did not differ significantly in their IgG or HAI responses to influenza vaccination or in levels of IFN-γ and IL-4. However, it remains unclear whether the “preserved” immune response of these younger caregivers was due to (1) an absence of immune senescence, (2) a relative absence of psychological morbidity, or both.     

Effects of combined stress during intense training on cellular immunity, hormones and respiratory infections

OBJECTIVES: This study was designed to determine immune and hormonal changes and their relationship with the incidence of upper respiratory tract infections (URTIs) during an extremely stressful military training (3 weeks of physical conditioning followed by a 5-day combat course with energy restriction, sleep deprivation and psychological stress). METHODS: Blood samples were collected from 21 cadets (21 +/- 2 years old) before training and after the combat course for analysis of leukocyte and lymphocyte subpopulations, serum cytokines [interleukin-6 (IL-6), IL-1beta and IL-10], and hormones [catecholamines, cortisol, leptin, total insulin-like growth factor I (IGF-I), prolactin, dehydroepiandrosterone sulfate (DHEAS) and testosterone]. Symptoms of URTI were recorded from health logs and medical examinations during training. RESULTS: After the combat course, total leukocyte and neutrophil counts were significantly increased while total lymphocytes were unchanged. In lymphocyte subsets, NK cells were reduced (p < 0.01), while CD4+ and CD19+ (B) cells were increased. Levels of IL-6 were increased (p < 0.01), while those of IL-1beta and IL-10 were unchanged. Norepinephrine and dopamine levels were increased, while those of cortisol were reduced. Levels of leptin, testosterone, prolactin and total IGF-I were reduced, while those of DHEAS were increased. The incidence of URTI increased during the training (chi(2) = 53.48, p < 0.05). After training data analysis showed a significant correlation between URTIs and NK cells (p = 0.0023). Training-induced changes in immune and hormonal parameters were correlated. CONCLUSIONS: Blood NK cell levels are related to increased respiratory infections during physical training in a multistressor environment. The training-induced decreases in immunostimulatory hormone levels may have triggered immunosuppression.     

Effects of interferon-beta therapy on innate and adaptive immune responses to the human endogenous retroviruses HERV-H and HERV-W, cytokine production, and the lectin complement activation pathway in multiple sclerosis

The effects of treatment of multiple sclerosis patients with IFN-β on elements in the innate and adaptive immune response were analysed in a longitudinal study. We demonstrate significant decreases in anti-Envelope antibody reactivity for the two closely related Gammaretroviral human endogenous retroviruses (HERVs), HERV-H and HERV-W, as a consequence of IFN-β therapy, closely linked to efficacy of therapy/low disease activity. We also show strong indications of a protective effect of high levels of two components in the innate pathogen-associated molecular pattern recognition: mannan-binding lectin (MBL), and MBL-associated serine protease 3 (MASP-3).Serum levels of typical Th1- and Th2-related, MS-relevant cytokines were also monitored. Overall both Th1- and Th2-associated cytokines were modestly, albeit significantly up-regulated, notably IL-2 and TNF-α (MS patients with inactive disease), as well as IL-4 and, to some extent IL-10 (no increase in IL-10 for MS patients with active disease (non-responders)). We found no overall changes in Th1/Th2 ratios.Our results support that HERV-H/HERV-W and the antiviral immune response may play a role in MS development, and that these HERVs have potential as biomarkers for disease activity.     

A longitudinal study on IL-2, sIL-2R, IL-4 and IFN-gamma in multiple sclerosis CSF and serum.

The cerebrospinal fluid (CSF) and serum levels of interleukin-2 (IL-2), soluble IL-2 receptor (sIL-2R), interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) were longitudinally investigated in 20 multiple sclerosis (MS) patients. There were 80 paired CSF and serum samples (range 2-8 per patient) covering a 1-5 year (mean 2.5 year) period. Increased levels of IL-2 and sIL-2R were found in 56 and 71%, respectively, of MS sera. In all patients, one or several sera (totally 89%) exhibited values above the normal range for either one of the components or both. The occurrence of IL-2 or sIL-2R positive CSF specimens was much lower, 15 and 9%, respectively. Only 3 MS sera (from one patient) had clearly detectable IL-4 and no CSF samples were definitely positive. IFN-gamma was undetectable in all serum and CSF specimens. No correlations were found between the immunological parameters and the clinical disease activity. The cytokine patterns in MS give strong support for the presence of a systemic T-cell activation. Furthermore, the data argue for a predominant activation of an IL-2- and sIL-2R-producing but not IL-4-producing T-helper (Th) lymphocyte subpopulation, Th1/CD4 + CD45R + cells.     

Intrathecal immune response in meningeosis neoplastica: IgG, IgM, oligoclonal bands and cytokines]

Owing to improved systemic control of widespread malignancy, neurological complications have become a major outcome factor and determinant of life quality in oncological patients. While solitary cerebrospinal metastases are often amenable to surgical and radiological treatment, the management of diffuse leptomeningeal neoplasia, mostly using combined radiochemotherapy, is still very difficult. Immunomodulative approaches represent a therapeutic alternative with increasing potential. We have analysed the natural immune response to leptomeningeal tumor invasion in 43 Patients by assessing cerebrospinal fluid (CSF) levels of albumin, IgG, IgM, interleukins (IL) 1, 2, 4 and 6, soluble IL-2 receptor (sIL-2R), interferon gamma (IFN gamma), tumor necrosis factor alpha (TNF alpha), and the tumor markers, carcinoembryonic antigen (CEA) and alphafetoprotein (AFP). In most patients, either elevated IgG index, IgM index, CSF IL-6, or detection of CSF oligoclonal immunoglobulin bands indicated a host reaction against tumor cells. IL-1, IL-2, and IL-4 were never detected in CSF or serum. sIL-2R and IFN gamma were rarely detected and were not associated with specific malignancies. CSF TNF alpha was only detected in melanoma patients and may be a specific indicator of that neoplasm. No correlation was found between levels of the tumor markers, CEA and AFP, and parameters of the immune response such as IgG, IgM or IL-6. The demonstration of intrathecal immune activation in a majority of patients with leptomeningeal neoplasia may offer a new option for immunomodulative oncological therapy.