The primary goal of this study is to test whether 12 weeks of high-intensity aerobic exercise can treat fatigue in Parkinsons disease (PD).

The study will be a randomized multi-site controlled trial with follow up. Clinically fatigued persons with PD will be allocated to either 12 weeks of high-intensity aerobic exercise or to a waitlist control group receiving high-intensity resistance exercise after 24 weeks of habitual lifestyle (control period).

It is hypothesized that persons with PD receiving 12 weeks of high-intensity aerobic exercise will show superior effects on perceived fatigue (i.e., clinical relevant reductions) when compared to the PD control group (primary hypothesis), and that these effects are sustained after 12-weeks of follow up (secondary hypothesis).

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.

Inclusion Criteria:

• Minimum 40 years
• Diagnosed with Idiopathic Parkinsons disease
• Stable in medical treatment for six month
• Able to transport themselves to and from exercise and testing sessions (with or without assistance)
• H&amp;Y score of three or lower

Exclusion criteria:

• Performing high-intensity exercise more than two times per week
• Significant medical comorbidities such as cardiovascular, respiratory, orthopedic, metabolic, or other neurological disorders
• Cognitive dysfunction that prevents following or understanding instructions related to training and testing (answering questionnaires)
• Known depression or alcohol abuse