| Field |
Value |
| NCT ID |
NCT06324422 |
| Status |
Recruiting |
| Phase |
Not Applicable |
| Sponsor |
University of Aarhus |
| Enrollment |
94 participants |
| Start Date |
January 2024 |
| Completion Date |
December 2025 |
This prospective cohort study evaluates the effectiveness of structured exercise interventions in treating Parkinson's Disease-related fatigue. Fatigue is one of the most common and disabling non-motor symptoms in PD, affecting up to 70% of patients.
Parkinson's disease fatigue (PDF) is a distinct phenomenon from general tiredness, characterized by:
- Disproportionate exhaustion relative to activity level
- Failure to complete tasks due to premature tiredness
- Morning fatigue that persists regardless of rest
- Physical and mental components that compound each other
The trial employs a structured exercise program typically including:
- Aerobic training (walking, cycling)
- Resistance training
- Balance exercises
- Flexibility and stretching routines
Fatigue in PD involves multiple overlapping pathophysiological mechanisms:
-
Dopaminergic dysfunction: Loss of dopaminergic neurons in the substantia nigra affects motor planning and execution, requiring greater cognitive effort for movements that become automatic in healthy individuals. This increased cognitive load contributes to perceived fatigue.
-
Neurotransmitter alterations: Beyond dopamine, PD involves dysfunction in:
- Serotonergic systems (affecting mood and energy regulation)
- Noradrenergic systems (affecting arousal and alertness)
- Acetylcholine (affecting attention and muscle function)
-
Neuroinflammation: Chronic neuroinflammation involving microglial activation and elevated cytokines (IL-1β, TNF-α, IL-6) contributes to fatigue through:
- Direct effects on brain energy metabolism
- Altered hypothalamic-pituitary-adrenal (HPA) axis function
- Sleep disturbance amplification
-
Cortical dysfunction: Functional imaging studies show altered activity in:
- Prefrontal cortex (executive function, task planning)
- Anterior cingulate cortex (attention, effort allocation)
- Basal ganglia (motor automaticity)
-
Muscle abnormalities:
- Reduced mitochondrial function in skeletal muscle
- Altered muscle fiber type distribution
- Impaired calcium handling
-
Cardiovascular dysregulation:
- Orthostatic hypotension
- Reduced baroreflex sensitivity
- Impaired heart rate variability
-
Sleep fragmentation:
- REM sleep behavior disorder
- Periodic limb movements
- Nocturnal akinesia
Exercise benefits PD fatigue through multiple pathways:
-
Neurotrophic factor release: Exercise increases Brain-Derived Neurotrophic Factor (BDNF), which:
- Promotes survival of remaining dopaminergic neurons
- Enhances synaptic plasticity in motor circuits
- Improves dopamine release and reuptake dynamics
-
Dopamine availability: Exercise may enhance:
- Tyrosine hydroxylase activity (rate-limiting step in dopamine synthesis)
- Vesicular monoamine transporter 2 (VMAT2) function
- Dopamine receptor sensitivity
Regular exercise exerts systemic anti-inflammatory effects:
- Reduced circulating pro-inflammatory cytokines
- Increased anti-inflammatory cytokines (IL-10)
- Improved gut microbiome diversity (reduced systemic inflammation)
- Enhanced lymphatic clearance of brain metabolites
Exercise stimulates:
- PGC-1α activation (master regulator of mitochondrial biogenesis)
- Increased mitochondrial density in muscle and brain
- Enhanced ATP production efficiency
- Reduced oxidative stress markers
Aerobic exercise improves:
- Cerebrovascular reactivity
- Endothelial function
- Angiogenesis in brain tissue
- Clearance of metabolic waste via glymphatic system
The trial likely follows evidence-based exercise recommendations for PD:
| Component |
Recommendation |
Frequency |
| Aerobic |
30 min moderate-intensity |
3-5x/week |
| Resistance |
8-10 exercises, 2-3 sets |
2-3x/week |
| Balance |
Standing tasks, dual-tasking |
Daily |
| Flexibility |
Stretching major muscle groups |
Daily |
| gait training |
Treadmill, overground |
3x/week |
Moderate intensity target: 40-70% heart rate reserve, or Rating of Perceived Exertion (RPE) 12-14 on Borg Scale
The FSS is a 9-item questionnaire assessing the impact of fatigue on daily functioning:
- Scores range from 9 (no fatigue impact) to 63 (severe fatigue impact)
- A score ≥ 4 indicates clinically significant fatigue
- Minimally important difference: 0.5-1.0 points per item
The PFS is a PD-specific fatigue measure:
- 16 items covering physical and mental fatigue
- Scores converted to 0-100 scale
- Higher scores indicate greater fatigue
- Measures functional exercise capacity
- Normative: >450m for healthy adults >60 years
- PD values typically 300-400m; improvements of 30-50m are clinically meaningful
Assesses quality of life across 8 domains:
- Mobility (0-100)
- Activities of Daily Living (0-100)
- Emotional Well-being (0-100)
- Stigma (0-100)
- Social Support (0-100)
- Cognitions (0-100)
- Communication (0-100)
- Bodily Discomfort (0-100)
- Measures daytime sleepiness
- Scores 0-24; >10 indicates excessive daytime sleepiness
- Common in PD due to sleep fragmentation
- Screens for depression
- 21 items, scores 0-63
- Depression and fatigue often co-occur in PD
¶ Current Treatment Landscape
Pharmacological options for PD fatigue are limited:
- Modafinil: Mixed evidence, not FDA-approved for PD fatigue
- Methylphenidate: May improve fatigue but has abuse potential
- Dopamine agonists: May help some patients but can worsen fatigue in others
- Antidepressants: May help if depression contributes
This creates a significant treatment gap that exercise can address.
Beyond fatigue, exercise provides:
- Motor symptoms: Slowed progression, improved mobility
- Non-motor symptoms: Sleep, mood, cognition
- Cardiovascular health: Reduced cardiovascular mortality
- Bone health: Osteoporosis prevention
- Fall prevention: Improved balance and strength
- Social engagement: Group exercise reduces isolation
Key barriers to exercise in PD:
- Fatigue itself (cycle of inactivity → deconditioning → more fatigue)
- Motor fluctuations ("on" vs "off" periods)
- Freezing of gait
- Orthostatic hypotension
- Fear of falling
- Access to specialized exercise programs
- Age 40-80 years
- Parkinson's Disease diagnosis (UK Brain Bank criteria or equivalent)
- Clinically significant fatigue (Fatigue Severity Scale ≥ 4)
- Able to perform exercise safely
- Stable PD medication (no changes in past 4 weeks)
- Severe cardiovascular disease (unstable angina, recent MI, severe heart failure)
- Orthopedic limitations preventing exercise
- Active depression requiring medication change
- Uncontrolled sleep disorders (severe sleep apnea, narcolepsy)
- Dementia precluding safe participation
- Uncontrolled medical conditions (diabetes, hypertension)
The University of Aarhus in Denmark is a leading European center for movement disorders research, with expertise in:
- Parkinson's disease rehabilitation
- Exercise physiology
- Neuroimaging of movement disorders
- Clinical trial methodology
This trial contributes to the growing evidence base for exercise as medicine in PD. Results may inform:
- Guidelines for exercise prescription in PD fatigue
- Healthcare coverage for exercise programs
- Development of tailored exercise interventions
- Biomarkers predicting exercise response
- ClinicalTrials.gov: NCT06324422
- Fatigue in Parkinson's Disease: Current Concepts and Future Prospects (2022)
- Exercise Therapy for Parkinson's Disease: Mechanisms and Clinical Applications (2023)
- Brain-Derived Neurotrophic Factor and Exercise in Parkinson's Disease (2021)
- Neuroinflammation in Parkinson's Disease: Role of Exercise (2022)