Background:
Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive and
disabling motor and non-motor symptoms. Worldwide, PD is the fastest growing neurological
disorder. Medical and surgical approaches in the symptomatic treatment of PD are progressing,
but currently no disease modifying therapies exist. While awaiting effective disease
modifying therapies, there is a major need to optimise symptomatic treatments of disabling PD
symptoms.
A recent survey among 678 persons with PD (pwPD) and 104 carer/partner/family members or
friends identified "Fatigue and energy" as the non-motor symptom that, if improved, would
make the most marked difference to their daily lives. Fatigue affects 30-70% (depending on
definition) of pwPD, and has been associated with worse prognosis, depression, anxiety, poor
sleep, limited working ability, social distancing, decreased physical activity and impaired
quality of life. Nevertheless, no effective medical or non-medical treatments exist for
fatigue in PD.
Generally, physical exercise is highly recommended as a symptomatic intervention in PD. In a
recent survey, 19% of pwPD (n=195) reported exercise as a coping strategy for fatigue and
approximately half of the participants (49.7%, n=511) reported that exercise improved
fatigue. However, it was not specified whether exercise was used as an acute coping strategy
that instantly reduced/prevented fatigue, or if it was used as a chronic coping strategy,
where regular exercise sessions reduced the chronic fatigue level. In other populations a
physical exercise session can acutely lower the perceived fatigue level, while increasing the
perceived energy level. To our knowledge, no studies have so far investigated the acute
effects of different types of high intensity exercise on fatigue in pwPD.
Diverging evidence exists on the effects of regular exercise on fatigue in PD. Two thirds of
the existing studies cautiously suggest that exercise (i.e., dance, aerobic exercise,
exergaming, and mixed modalities) can potentially improve perceived fatigue. However, the
last third show no difference or even increased fatigue levels following an exercise
intervention. These heterogeneous results may be due to poor study designs as only one study
applied fatigue as the primary outcome making most existing studies at risk of being
underpowered. Also, none of the studies applied "clinical fatigue" as an inclusion criterium,
which might have led to an underestimation of the potential exercise effects. Lastly, most
existing studies were based on small sample sizes (i.e., <30 participants), half included no
control group and most interventions prescribed exercise with low to moderate intensity
(rather than higher intensity exercise), potentially limiting the effects of the
intervention. Consequently, there is a need for a new PD high intensity exercise study with
stronger methodologies assessing the chronic effects on fatigue.
Another argument for further evaluation of exercise as a treatment for fatigue in pwPD is
based on findings from other neurological disorders such as multiple sclerosis, where both
aerobic- and resistance exercise effectively reduce self-reported fatigue. Nonetheless, it
remains unclear whether some exercise modalities are more efficient than others at inducing
acute and chronic effects, making aerobic- and resistance exercise relevant for testing in
pwPD.
Taken together, there is a need to investigate if high-intensity exercise can decrease
fatigue in clinically fatigued pwPD, both acutely (i.e., effects observed immediately after a
single exercise session) and/or chronically (i.e., the general fatigue level after a period
with regular exercise sessions). Understanding the efficacy of basic exercise modalities
(i.e., aerobic- and resistance exercise) and their working mechanisms before applying mixed
exercise modalities therefore seems essential in the development of new fatigue management
interventions for pwPD.
To gain further insight into the effects of high-intensity exercise on fatigue in PD, a
randomized controlled multi-site trial with a follow up was designed.
As the present study may pave the way for introducing exercise in the management of PD
fatigue, the study poses the potential to change clinical practice for pwPD.
The purpose of the mother study is to test the hypotheses that clinically fatigued pwPD
receiving aerobic exercise will show superior effects on fatigue (i.e., clinical relevant
reductions) when compared to a control group (primary hypothesis), and that these effects are
sustained after 12 weeks of follow up (secondary hypothesis).
Interventions:
Aerobic exercise: 12 weeks, with 2-3 sessions per week, of supervised high intensity
progressive aerobic exercise are performed comprising continuous and/or interval cycling-,
rowing- or cross-trainer sessions, increasing from 30 towards 60 min with intensity
increasing from 65 to 90% of individual maximum heart rate.
Resistance exercise: 12 weeks, with 2-3 sessions per week, of supervised resistance exercise
are performed comprising machine exercises in 3 to 5 sets with 2-3 minutes rest in between
and a decrease from 12 to 6 repetitions in parallel with intensity increasing from 15RM
(repetition maximum) to 8 RM.
The exercise interventions have previously been used by our research group in neurological
populations and are safe and feasible. Interventions are allowed to run up to 14 weeks to
catch up missing exercise sessions.
Outcomes:
See the section "Outcome Measures" for specifications. Additionally, contact information,
demographic information, health and medication information, and a blood sample will be
obtained
Statistical considerations:
Whilst fatigue has been reported to decrease in pwPD after exercise interventions, none of
the existing studies have applied the Modified Fatigue Impact Scale (MFIS). In fatigued
persons with multiple sclerosis (MFIS ≥38 points) our group has previously shown that the
total MFIS score can be substantially reduced following aerobic exercise (change scores:
exercise -13±16 vs. control -3±16)28. By expecting comparable effects in fatigued pwPD, our
sample size estimation (alpha level 5%, beta level 80%) revealed that a minimum of 84 pwPD
must be enrolled in the study (i.e., n=42 for the aerobic exercise group and n=42 for the
control group/waitlist resistance exercise group). Assuming a dropout of 10%, n=47
participants are required in each group.
Randomization:
After baseline assessment of fatigued participants, participants will be randomized in a 1:1
ratio to aerobic exercise or a waitlist control group. A computer-generated list of random
numbers will be generated in the Research Electronic Data Capture (REDCap) system. The
randomization will be stratified by site. The outcome assessors will be blinded for the
randomization.
Perspectives:
The findings of this project hold the potential to establish aerobic exercise and/or
resistance exercise as a safe and accessible treatment(s) of a frequent and disabling PD
non-motor symptom, namely fatigue. In addition, the proposed study will expand our current
knowledge about the acute effects of exercise on fatigue, potentially offering a simple
modality to manage fatigue during everyday life. Taken together, the present study may lay
the ground for a yet unexplored area of research with important implications for millions of
pwPD, clinicians and the society.
