Multiple Sclerosis Clinical Trial
Official title:
Intensity-dependent Impacts of Training on Growth Factors BDNF and Cognitive Functions in Persons With Multiple Sclerosis - a Single-center Randomized Controlled Trial
Multiple Sclerosis (MS) is a chronic immune-mediated disease of the central nervous system,
accompanied by varying inflammatory manifestations, demyelinization and axonal loss. With
chronic progressive or relapsing-remitting disease onsets persons with MS (pwMS)
progressively develop impaired functional capacity and show reduced physical activity and
cognitive decline compared to healthy controls. The primary aims of rehabilitation in pwMS
are therefore to increase levels of activity and participation leading to increase
independence of the participants. In general exercise ranges from passive physiotherapy-based
interventions to submaximal endurance training sessions. Current recommendations advise pwMS
that exercise should be matched with the individual performance capacities. Exercise training
in pwMS then has the potential to target and improve many components outlined in the
ICF-model.
Cytokines and neurotrophic factors have received increased attention in MS research and
addressed the brain-derived neurotrophic factor (BDNF) as an important mediator of neuronal
regeneration linking the effects of exercise with MS pathogenesis. Data show positive
connections between elevated neurotrophin concentrations, induction of neuroplasticity,
recovery of the motor and cognitive functions and the applied training intensities.
Similarly, intensive and progressive exercise bouts seem to have greater benefits on
cardiorespiratory fitness and maximum voluntary strength in elderly and seniors with
dementia. Therefore, specific exercise prescriptions may be necessary for targeting the
specific impairments also in pwMS.
This study aims to evaluate two different training modalities (intensive versus normal) in
pwMS. It is expected that both modalities will improve cardiorespiratory fitness and
cognitive functions in pwMS. Based on the findings that higher training intensities
facilitate greater benefits, it is expected that pwMS will tolerate the intensive training
intensities and show positive connections to elevated neurotrophin concentrations.
The results will to help to clearer understand the benefits of each type of exercise conveyed
for pwMS and will assist in the development of patient-specific exercise prescriptions.
This study aims to evaluate two different training modalities (intensive versus normal) in
pwMS. It is expected that both modalities will improve cardiorespiratory fitness and
cognitive functions in pwMS. Based on the findings that higher training intensities
facilitate greater benefits, it is expected that pwMS will tolerate the intensive training
intensities and show positive connections to elevated neurotrophin concentrations.
Primary outcomes are the acute (after CPET) and chronic (3-week training intervention)
changes of neurotrophic factors and cognitive functions. All other measures are secondary
outcomes (Training values: VO2peak, Workload, Heart rate; Fatigue: FSMC; Anxiety and
Depression: HADS.
Participants are eligible if they hold a definite diagnosis of multiple sclerosis (revised
McDonald criteria), an EDSS score of 1.0 -6.0, they give no written consent, severe
cardiovascular exacerbations (RR > 240/120, HR above the age predicted maximum of 220-Age)
are persistent, they hold severe cognitive impairments, they face severe disease progression
or relapses.
Main measurements and procedures include:
Blood sampling: Blood samples (10ml) of the primary outcomes will be taken by vein puncture
from the antecubital vein in a seated position before the exercise bout and straight after
reaching VO2peak during cool down, with the participant still seated on the ergometer.
Before samples are taken the participant will be required to relax for 10 minutes, blood
sampling will take approximately 5 minutes.
Cardiopulmonary Exercise Test (CPET): Cardiorespiratory fitness is assessed through a
progressive CPET performed at baseline on a cycle ergometer at t1 and is repeated the day
prior to discharge at t2.
The exercise protocol consists of (a) first 3 minutes at rest (no pedalling) on the cycle
ergometer; (b) 3 minutes of unloaded pedalling as a warm up; (c) testing phase until the
participant reaches a symptom limited maximum. Workload is continuously ramp type increased
by 5-10 Watts every minute to ensure 8-12 minutes of testing; (d) the final 3 minutes are
unloaded pedalling to cool down. Heart rate (Polar Electro, Kempele, Finland) and blood
pressure (Riva-Rocci) are monitored for the last 10 seconds every 2 minutes during the test.
The 10-point BORG scale therapy short-form assesses the rate of perceived exertion (RPE) at
phases (c) and (d). Blood samples are drawn at rest prior to phase (a) and at the end of CPET
phase (d) at t1 and t2
Cognitive assessments: Cognitive assessments will be performed using the German version of
the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). Additionally,
the German version of the Trail-Making-Pencil-Test versions A/B (TMT-A/B) and Go/noGo (TAP
version) will be used. Cognitive assessments will be performed at baseline (t1) and repeated
at t2.
Fatigue: Fatigue is assessed with the multidimensional FSMC scale before CPET under resting
conditions. FSMC has defined cut-off scores to classify mildly, moderately and severely
fatigued patients. Cut-off for fatigue is set for the total score at 43 and for the motoric
and cognitive sub-scores at 22. The scale has a proven test-retest liability and has been
translated into multiple languages.
Depression and Anxiety: Depression and anxiety are assessed with the Hospital Anxiety and
Depression Scale (HADS). The HADS is a self-assessment questionnaire for adults with physical
ailments that assess anxiety and depression. The questionnaire consists of 14 items seven for
anxiety seven for depression with higher scores indicating anxiety or depression.
Training: Endurance training in both groups consisted of physiologically defined heart rate
controlled cycling at 50-60 rounds per minutes (rpm) and progressive resistance training. All
participants will be stratified according to their cardiorespiratory fitness and level of
cognitive fatigue in to group Intensive Training (IT) and Normal Training (NT). Training
groups differ in the applied intensities and frequencies.
The IT will train less frequent but training sessions will be more intensive in its effects.
Training will be performed daily in six sessions (three morning and three afternoon
sessions), synchronized and individually matched to a ratio of active versus passive sessions
of 2:1.
The NT is the normal training performed out of the daily routine and outlines the usual care
of the Valens clinic. Training will be performed in maximal eight training sessions and will
not be synchronized and not individually matched to a ratio of active versus passive
sessions.
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