Zum differentiellen Einfluss von hoch-intensivem Intervall- und moderat kontinuierlichem Ausdauertraining auf die kognitive Leistungsfähigkeit bei Personen mit Multiple Sklerose

Regelmäßiges körperliches Training kann bei vielen Multiple Sklerose (MS) spezifischen Symptomen positive Effekte hervorrufen. Einheitliche Evidenz zu den Effekten körperlichen Trainings auf die kognitive Leistungsfähigkeit existiert jedoch aufgrund verschiedener methodischer Limitationen und heterogenen Designs bestehender Untersuchungen nicht. Zugrundeliegende mechanistische Wirkweisen potentieller Verbesserungen bleiben ebenfalls weitestgehend ungeklärt. Neurofilament-Leichtketten-Proteine (NfL) als Biomarker für neurodegenerative Prozesse könnten möglicherweise zur Aufklärung mechanistischer Wirkweisen von körperlichem Training beitragen und als potentielles Bindeglied zwischen molekularen Mechanismen und neuropsychologischen Messverfahren der kognitiven Leistungsfähigkeit dienen. Die vorliegende Dissertation umfasst vier Publikationen. Ergebnisse der Publikationen 1-3 zeigen, dass der kognitive Status bei Studieneinschluss (eingeschränkte/ intakte kognitive Leistungsfähigkeit) ein Einflussfaktor für die Veränderung der kognitiven Leistungsfähigkeit in Folge einer dreiwöchigen Ausdauertrainingsintervention (hoch intensives Intervalltraining vs. Moderat kontinuierliches Training) zu sein scheint. Dabei profitierten Personen mit MS, die zu Studieneinschluss kognitive Einschränkungen aufwiesen signifikant stärker von der Trainingsintervention hinsichtlich einer Verbesserung der kognitiven Leistungsfähigkeit, als Personen, die keine Einschränkungen aufwiesen (Publikation 1 & 2). Bei Studieneinschluss wurde eine Assoziation zwischen pNfL und der kognitiven Leistungsfähigkeit erkannt. Insbesondere HIIT verglichen zu MCT induzierte eine Reduktion von pNfL-Konzentrationen nach einer akuten Trainingseinheit, welche ebenfalls drei Stunden nach Beendigung der Belastung messbar war. Nach der dreiwöchigen Trainingsintervention wurden hingegen keine Effekte auf die pNfL-Konzentration beobachtet (Publikation 3). Die Ergebnisse der vorliegenden Arbeit liefern relevante Erkenntnisse für die Gestaltung künftiger Studien, bei denen zur Untersuchung der Effekte körperlichen Trainings auf die kognitive Leistungsfähigkeit von MS-Betroffenen ausschließlich Personen eingeschlossen werden sollten, welche kognitive Einschränkungen aufweisen. Ob hoch-intensive Intervallbelastungen in der Tat moderater kontinuierlicher Belastung hinsichtlich der Effekte auf die kognitive Leistungsfähigkeit bei Personen mit MS überlegen sind, sollte in künftigen großangelegten randomisiert-kontrollierten Studien mit Kognition als primärem Endpunkt, einem längeren Interventionszeitraum und weiteren Interventionsgruppen sowie einer passiven Kontrollgruppe untersucht werden. Ferner bedarf es langfristiger Interventionsstudien zur Untersuchung chronischer Effekte auf die Veränderung der pNfLKonzentration und dessen potentielle Assoziationen zur kognitiven Leistungsfähigkeit. In künftigen Studien sollte außerdem der Frage nachgegangen werden, inwiefern ein regelmäßiges Training bei noch nicht eingeschränkten MS-Betroffenen das Auftreten der kognitiven Einschränkung womöglich im fortschreitenden Krankheitsverlauf zeitlich verzögert. Die Relevanz der kognitiven Funktion als Ziel der Bewegungstherapie wird letztlich in Publikation 4 der vorliegenden Arbeit fokussiert

Cycling in primary progressive multiple sclerosis (CYPRO): study protocol for a randomized controlled superiority trial evaluating the effects of high-intensity interval training in persons with primary progressive multiple sclerosis

Background: Primary progressive multiple sclerosis (PPMS) is the least prevalent multiple sclerosis (MS) phenotype. For persons with PPMS (pwPPMS), pharmacological treatment options are limited. As a complementary non-pharmacological treatment, endurance training improves the health-related quality of life (HRQoL), numerous MS symptoms, and MS-related performance impediments. High-intensity interval training (HIIT) has been shown to induce superior effects compared to moderate-intensity continuous training (MCT). As current evidence is based on MS samples with mixed phenotypes, generalizability to pwPPMS remains unclear. Methods: CYPRO is a parallel-group, single-center, and single-blind randomized controlled superiority trial evaluating the effects of HIIT compared to MCT in pwPPMS. Sixty-one pwPPMS are randomized (1:1) to perform volume-matched HIIT or MCT sessions on bicycle ergometers two to three times per week in addition to standard rehabilitative care during their three-week inpatient stay at Valens rehabilitation clinic, Switzerland. Standard rehabilitative care comprises endurance and strength training, physiotherapy, and occupational therapy. HIIT sessions include six 90-second intervals at 95% peak heart rate (HRpeak), interspersed by 90-second active breaks with unloaded pedaling, aimed to reach 60%HRpeak. MCT represents the standard treatment at Valens rehabilitation clinic and is performed as continuous cycling at 60%HRpeak for the duration of 26 minutes. The primary outcome is cardiorespiratory fitness, assessed as peak oxygen consumption (V̇O2peak) during cardiopulmonary exercise testing (CPET). Secondary outcomes include peak power output during CPET, walking capacity, cognitive performance, HRQoL, fatigue, anxiety and depressive symptoms, and blood-derived biomarkers (e.g., serum neurofilament light chain, glial fibrillary acidic protein, kynurenine pathway metabolites) related to MS pathophysiology. All outcomes are assessed at baseline and discharge after three weeks. Venous blood sampling is additionally performed immediately and two hours after the first HIIT or MCT session. Discussion: CYPRO will expand current knowledge on symptom management and rehabilitation in MS to the subpopulation of pwPPMS, and will contribute to the exploration of potential disease-modifying effects of endurance training in MS. The superiority design of CYPRO will allow deriving explicit recommendations on endurance training design in pwPPMS that can be readily translated into clinical practice. Trial registration: CYPRO has been prospectively registered at ClinicalTrials.gov on 8 February 2022 (NCT05229861)

Fitness, physical activity, and exercise in multiple sclerosis

Background A moderate to high level of physical activity, including regular exercise, represents an established behavioral and rehabilitative approach for persons with multiple sclerosis (pwMS). Although being increasingly proposed to limit disease activity and progression, high-quality evidence is lacking. Objective The objective of the study is to provide valuable information for MS clinicians and researchers by systematically evaluating the current state of evidence (i) whether exercise interventions affect established clinical measures of disease activity and progression in pwMS (i.e., EDSS, relapse rate, lesion load, brain volume, MSFC) and (ii) how the physical activity and fitness level interact with these measures. Methods Literature search was conducted in MEDLINE, EMBASE, CINAHL, and SPORTDiscus. Evaluation of evidence quality was done based on standards published by The American Academy of Neurology. Results It is likely that exercise improves the MSFC score, whereas the EDSS score, lesion load, and brain volume are likely to remain unchanged over the intervention period. It is possible that exercise decreases the relapse rate. Results from cross-sectional studies indicate beneficial effects of a high physical activity or fitness level on clinical measures which, however, is not corroborated by high evidence quality. Conclusions A (supportive) disease-modifying effect of exercise in pwMS cannot be concluded. The rather low evidence quality of existing RCTs underlines the need to conduct more well-designed studies assessing different measures of disease activity or progression as primary end points. A major limitation is the short intervention duration of existing studies which limits meaningful exercise-induced effects on most disability measures. Findings from cross-sectional studies are difficult to contextualize regarding clinical importance due to their solely associative character and low evidence quality

Ingestion of colostrum from specific cows induces Bovine Neonatal Pancytopenia (BNP) in some calves

Background: Since 2006, cases of haemorrhagic diathesis in young calves have been observed with a much higher incidence than previously known. The syndrome, now uniformly called Bovine Neonatal Pancytopenia (BNP), is characterized by multiple (external and internal) haemorrhages, thrombocytopenia, leukocytopenia, and bone marrow depletion. Although various infectious and toxicological causes of bleeding disorders in calves have been ruled out, the aetiology of BNP remains unknown. However, field observations have led to the hypothesis that the aetiological principle may be transmitted to calves via colostrum. The objective of the present study was to verify whether ingestion of colostrum from dams of known BNP calves can elicit signs of BNP and typical haematological findings in conveniently selected neonatal calves. Six such calves received one feeding of colostrum (or a mixture of colostrum batches) from dams of known BNP calves. As controls, another six conveniently selected calves from herds which had never had a BNP case received one feeding of colostrum from their own dams. Haematological and clinical parameters were monitored. Results: One of the six experimental calves never showed any haematological, clinical or pathological evidence of BNP. In the other five calves, thrombocyte and leukocyte counts dropped within a few hours following ingestion of colostrum. Of those, three calves developed clinical signs of BNP, their post-mortem examination revealed bone marrow depletion. Of the remaining two calves, a pair of mixed twins, marked thrombocytopenia and recurrent leukocytopenia was evident in one, in which only slight changes in the bone marrow were detected, while in the other thrombocyte counts dropped, but rebounded later, and no bone marrow changes were noted. Thrombocyte counts of the experimental calves were statistically significantly lower than those of the control calves at 2 hours post ingestion of colostrum and at every sampling point between 9 hours and 8 days postcolostral. Leucocyte counts of the experimental calves were statistically significantly lower than those of control calves at 2 hours post ingestion of colostrum and 3-7 days postcolostral. Conclusions: BNP can be induced in some calves by ingestion of colostrum from cows that have given birth to BNP calves

Physical activity is related to disease severity and fatigue, but not to relapse rate in persons with relapsing remitting multiple sclerosis – a self-reported questionnaire based study

IntroductionBased on theoretical models, physical activity has been introduced as a promoting method to mitigate the disease severity, fatigue and relapse rate in multiple sclerosis. The primary objective of the study was to investigate the relation between self-reported physical activity level and disease severity, fatigue and relapse rate in persons with relapsing remitting multiple sclerosis (RRMS).MethodsA survey was offered to persons with RRMS from March 2019 to August 2021 (n = 253). Physical activity level, fatigue and disease severity were determined using the Godin Leisure-Time Questionnaire (GLTEQ), the Patient Determined Disease Steps (PDDS) scale and the Fatigue Scale for Motor and Cognitive Functions (FSMC). Additionally, participants’ relapse rate was recorded.ResultsBivariate correlations revealed an inverse relation between physical activity level and PDDS (ρ = −0.279; p < 0.001) as well as between physical activity and FSMC (r = −0.213, p < 0.001), but not between physical activity and relapse rate (r = 0.033, p > 0.05). Multiple linear regression analyses explained 12.6% and 5.2% of the variance of PDDS and FSMC.ConclusionOur findings confirm a relation between self-reported physical activity, disease severity and fatigue in persons with RRMS. However, self-reported physical activity level does not seem to affect the annualised relapse rate

Multivalent display of minimal Clostridium difficile glycan epitopes mimics antigenic properties of larger glycans

Synthetic cell-surface glycans are promising vaccine candidates against Clostridium difficile. The complexity of large, highly antigenic and immunogenic glycans is a synthetic challenge. Less complex antigens providing similar immune responses are desirable for vaccine development. Based on molecular-level glycan–antibody interaction analyses, we here demonstrate that the C. difficile surface polysaccharide-I (PS-I) can be resembled by multivalent display of minimal disaccharide epitopes on a synthetic scaffold that does not participate in binding. We show that antibody avidity as a measure of antigenicity increases by about five orders of magnitude when disaccharides are compared with constructs containing five disaccharides. The synthetic, pentavalent vaccine candidate containing a peptide T-cell epitope elicits weak but highly specific antibody responses to larger PS-I glycans in mice. This study highlights the potential of multivalently displaying small oligosaccharides to achieve antigenicity characteristic of larger glycans. The approach may result in more cost-efficient carbohydrate vaccines with reduced synthetic effort

Influence of combined functional resistance and endurance exercise over 12 weeks on matrix metalloproteinase-2 serum concentration in persons with relapsing-remitting multiple sclerosis-a community-based randomized controlled trial

Background: The relevance of regular moderate to intense exercise for ameliorating psychomotor symptoms in persons with multiple sclerosis (pwMS) is becoming increasingly evident. Over the last two decades, emerging evidence from clinical studies and animal models indicate immune regulatory mechanisms in both periphery and the central nervous system that may underlie these beneficial effects. The integrity of the blood-brain barrier as the main structural interface between periphery and brain seems to play an important role in MS. Reducing the secretion of proteolytic matrix metalloproteinases (MMP), i.e. MMP-2, as disruptors of blood-brain barrier integrity could have profound implications for MS. Methods: In this two-Armed randomized controlled trial 64 participants with relapsing-remitting MS (RRMS) (EDSS 0-4.0) will be allocated to either an intervention group or a passive wait list control group. The intervention group will perform 60 min of combined functional resistance and endurance exercises 3x per week over a period of 12 weeks in a community-based and publicly available setting. Changes in serum concentration of MMP-2 will be the primary outcome. Secondary outcomes are numbers of immune cell subsets, soluble (anti-) inflammatory factors, physical capacity, cognitive performance, physical activity behavior, gait performance, and patient-reported outcomes. All outcome measures will be assessed at baseline and after week 12 with an additional blood sampling before, during and immediately after a single training session in week 6. Discussion: To our knowledge, this will be the first RCT to investigate both the acute and chronic effects of a community-based intense functional resistance and endurance exercise regimen in persons with RRMS. Combining analysis of biological and cognitive or psychological outcomes may provide a better understanding of the MS-specific symptomology. Trial registration: DRKS00017091; 05th of April, 2019; International Clinical Trials Registry Platform

Incidence of bovine neonatal pancytopenia in 243 farms in Germany

Background: Several research groups from different European countries have worked on the aetiopathogenesis of bovine neonatal pancytopenia (BNP) and an association between the use of the vaccine PregSure BVD (Pfizer, Germany) and the development of this haemorrhagic disease was confirmed. Because BNP is not a notifiable disease, it is difficult to obtain information on its incidence. Based on pharmacovigilance (PhV) data, which are the only officially available data at the national level, the incidence of BNP is considered low. However, voluntary reporting of the disease can lead to underreporting. To gain more insight into the incidence of BNP among the affected herds, an epidemiological study was performed, which focused on 243 farms in Germany with cases of BNP. Farmers were asked to report the occurrence of BNP, including the number of cases, which allowed calculation of incidence in the affected herds. Matching such data with the registered cases in the National PhV System (NPhVS) gave us an opportunity to assess the extent of BNP underreporting. Results: On 243 farms, a total of 1195 calves younger than 4 weeks with haemorrhagic diathesis were registered. In 58 % of the reports, a diagnosis of BNP was confirmed by blood analysis and or by necropsy. The number of cases observed on individual farms ranged from 1 to 80. Based on these results, the incidence of BNP on affected farms ranged from 0.3 to 15.2 % (median 2.9 %). The maximal incidence in the year with the highest number of BNP calves ranged between 0.4 and 18.6 % (median 3.3 %). Comparing the number of cases registered in the NPhVS to the numbers found in this study revealed considerable underreporting to the national database: only 44 % of the farms and 41 % of the BNP calves included in the study were registered in the NPhVS. Conclusions: In spite of the opportunity to report BNP calves to the Paul-Ehrlich-Institut (Langen, Germany), the estimated number of undetected BNP cases is remarkably high. However, even if the revealed substantial underreporting is taken into account, the incidence of BNP is low. Nevertheless, the incidence on some affected farms is very high, resulting in considerable financial losses that should not be underestimated. Although the exact pathomechanism of BNP at the molecular level is still not known, its incidence is clearly declining following withdrawal of PregSure BVD from the market

Fitness, physical activity, and exercise in multiple sclerosis: a systematic review on current evidence for interactions with disease activity and progression

Background A moderate to high level of physical activity, including regular exercise, represents an established behavioral and rehabilitative approach for persons with multiple sclerosis (pwMS). Although being increasingly proposed to limit disease activity and progression, high-quality evidence is lacking. Objective The objective of the study is to provide valuable information for MS clinicians and researchers by systematically evaluating the current state of evidence (i) whether exercise interventions affect established clinical measures of disease activity and progression in pwMS (i.e., EDSS, relapse rate, lesion load, brain volume, MSFC) and (ii) how the physical activity and fitness level interact with these measures. Methods Literature search was conducted in MEDLINE, EMBASE, CINAHL, and SPORTDiscus. Evaluation of evidence quality was done based on standards published by The American Academy of Neurology. Results It is likely that exercise improves the MSFC score, whereas the EDSS score, lesion load, and brain volume are likely to remain unchanged over the intervention period. It is possible that exercise decreases the relapse rate. Results from cross-sectional studies indicate beneficial effects of a high physical activity or fitness level on clinical measures which, however, is not corroborated by high evidence quality. Conclusions A (supportive) disease-modifying effect of exercise in pwMS cannot be concluded. The rather low evidence quality of existing RCTs underlines the need to conduct more well-designed studies assessing different measures of disease activity or progression as primary end points. A major limitation is the short intervention duration of existing studies which limits meaningful exercise-induced effects on most disability measures. Findings from cross-sectional studies are difficult to contextualize regarding clinical importance due to their solely associative character and low evidence quality. PROSPERO registration number CRD42020188774