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NCT Number: NCT03808675

Aerobic Exercise in Parkinson's Disease

Parkinson's disease (PD) is an incurable brain illness that afflicts more than one million Americans, including many aging Veterans. PD places an unbearable burden on the individual due to progressive impairment of movement and mental function. As a result, patients lose critical abilities such as driving and can become isolated. Although drugs and surgery help movement problems, their benefits are temporary and may cause side effects. Drugs provide limited and temporary benefit for cognition and do not prevent dementia. Animal and preliminary human studies on aerobic exercise show promising results in helping a broad spectrum of symptoms. However, due to limited and inconsistent research results, the long term effects of aerobic exercise on brain health and clinical features in PD is unknown. The investigators will conduct a clinical trial to test the long term effects of aerobic exercise on the brain tissue, movement, mental functions, and driving in PD. If effective, aerobic exercise can be implemented immediately as a low cost, easily accessible treatment in PD.

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Key information

Conditions

Parkinson's Disease Adherence Interventions Basal Ganglia Diseases Behavior Behavioral Symptoms Brain Diseases Central Nervous System Diseases Depression Health Behavior Health Education Medication Adherence Motor Activity Movement Disorders Nervous System Diseases Neurodegenerative Diseases Parkinson Disease Parkinsonian Disorders Patient Acceptance of Health Care Patient Compliance Synucleinopathies Treatment Adherence and Compliance

Age range

40 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Iowa City VA Health Care System, Iowa City, IA, Iowa City, Iowa, United States

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About this study

Parkinson's disease (PD) culminates in dementia, immobility, and death at a huge societal cost. Even early in the course, motor and cognitive dysfunction impairs instrumental activities of daily living (IADL). Non-motor symptoms due to fatigue, mood, sleep, and autonomic disorders further reduce quality of life (QoL). DTI shows progressive decline in brain tissue integrity. Usual care of PD centers on medical and surgical treatments relieve motor symptoms, but these cause side effects and lose efficacy over time. Usual treatment for non motor manifestations with pharmaceuticals (e.g., antidepressants) is symptomatic and not specific for PD. Acetylcholine esterase inhibitors exert modest symptomatic benefits on dementia, but there is no approved treatment for mild cognitive impairment. Physical Therapy is usually prescribed in later stages when mobility impairment ensues. There is no approved standard exercise regimen for PD. There is no cure or disease modifying treatment. Thus, there is a critical need for treatments that provide broad spectrum of benefits and slow PD.

Preliminary research suggests that aerobic exercise has potential to meet this need. However, aerobic exercise is demanding and carries some risks. It is unknown if aerobic exercise is more beneficial than usual care in PD in long term due to gaps in the investigators knowledge about the effects of cardiorespiratory fitness (CRF) on brain tissue integrity, motor function, cognition, IADL, QoL, and disease progression. Limitations of current studies include short duration, small sample size, lack or inadequacy of controls, lack of outcome measures for cognition and IADL, and lack of biological markers to measure progression. The objective in this application is to fill the translational gap by determining the biological, clinical, and functional effects of long term aerobic exercise (LTAE) in PD.

The overall hypothesis is that LTAE improves brain tissue integrity and slows down PD. The FIRST AIM is to determine the effects of LTAE on clinical features and functional abilities in PD. The investigators' prior 6-month, uncontrolled trial showed preliminary evidence that aerobic exercise improves aspects of motor function, cognition, and QoL in PD, but long term outcomes and implication for functional abilities are unknown. The investigators hypothesize that LTAE will provide sustained improvement in motor function, cognition, and non-motor symptoms with translation of benefits to QoL and IADL. The investigators will test this with a one-year randomized controlled trial (RCT) that compares the effects of moderate aerobic exercise vs usual care. The investigators will use driving as the outcome for IADL. Driving represents an important symbol for independence, and depends on integrity of cognitive and motor systems. The SECOND AIM is to determine the mechanism of LTAE effects in PD. CRF reflects complex improvements in vascular, cardiac, and metabolic health from aerobic exercise. There is preliminary evidence that higher CRF is associated with better brain health and motor/cognitive function, and that aerobic exercise improves these outcomes. For example, the investigators' preliminary study showed improvement of microtissue integrity in the striatum and white matter on DTI, but it is unclear how these changes counteract PD progression over long term. The hypotheses are: 1) LTAE will improve brain tissue integrity as indexed by DTI, 2) LTAE effects on motor and cognitive function are mediated by changes in brain tissue integrity on DTI, and 3) physiological processes leading to improved CRF from AE are critical to the benefits on the brain tissue integrity and motor/cognitive function. The investigators will test these hypotheses determining the effects of LTAE on CRF and DTI, and the association between individual differences in training related changes in motor and cognitive function, DTI, and CRF.

In summary, the investigators' proposal leverages the diverse interdisciplinary team, strong preliminary data and past work, and unique infrastructure to determine if LTAE slows down neurodegeneration and clinical disability in PD.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Men or women aged 40 and older with the diagnosis of idiopathic PD per UK Brain Bank criteria
  • Hoehn-Yahr Stage I-III, on stable dopaminergic treatment regimen for equal or greater than 4 weeks prior to baseline.
  • Aerobic Fitness: VO2max below "very good" fitness levels for their age and gender at baseline cyle ergometry.

To include subjects who have room to improve their aerobic fitness, the investigators will enroll only those subjects whose VO2max is below "very good" fitness level (about 90% of the population) using age and gender based VO2max norms based review of 62 studies where VO2max was measured directly in healthy adult subjects in the USA, Canada and 7 European countries (Reference: Shvartz, E and Reibold, RC. Aerobic fitness norms for males and females aged 6 to 75 years: a review.

Aviat Space Environ Med. 1990; 61:3-11).

  • Cognitive function: No dementia per Movement Disorder Society Level I criteria (Reference: Dubois, B, Burn, D, Goetz, C, et al. Diagnostic procedures for Parkinson's disease dementia: recommendations from the movement disorder society task force. Mov Disord. 2007; 22:2314-2324).
  • Current active drivers with a valid driver's license
  • Veteran or non-veteran

Exclusion criteria

  • Subjects unwilling or unable to give informed consent
  • Secondary parkinsonism (e.g., drug induced)
  • Parkinson-plus syndromes
  • History of brain surgery for PD such as deep brain stimulation
  • Corrected visual acuity less than 20/50 (due to effect on driving)
  • Contraindications to exercise per ACSM criteria for Exercise Testing and Training (Reference: American College of Sports Medicine. Cardiorespiratory Exercise Prescription. In: Ehrman JK, ed. ACSM's Guidelines for Exercise Testing and Prescription.6th ed. Baltimore: Lippincott Williams & Wilkins, 2010:448-462).
  • No confounding acute or unstable medical, psychiatric, orthopedic condition. Subjects who have hypertension, diabetes mellitus, depression, or other common age related illness will be included if their disease under control with stable treatment regimen for at least 30 days.
  • Clinically significant TBI or PTSD
  • Presence of other known medical or psychiatric comorbidity that in the investigator's opinion would compromise participation in the study
  • Presence of dementia per Movement Disorder Society Level I criteria
  • Subjects with clinically significant depression as determined by a Beck Depression Inventory (BDI) score greater than 15 at the screening visit
  • History of exposure to typical or atypical antipsychotics or other dopamine blocking agents within 6 months prior to the baseline visit
  • Use of investigational drugs within 30 days before screening
  • Subjects have to be on a stable regimen of central nervous system acting medications (benzodiazepines, antidepressants, hypnotics) for 30 days prior to the baseline visit
  • Contraindication to having a brain MRI

Treatment and study plan

Aerobic Walking

Behavioral

The investigators will use self-administered continuous walking exercise at a moderate intensity level, defined as 40-59% of heart rate reserve or 64-77% of heart rate at gas exchange threshold (HRGET) by ACSM as in the investigators' preliminary study (PMID: 24991037 PMCID: PMC4132568). The HRGET will be determined as the heart rate at VO2max during graded cycle ergometry. The total duration of the exercises will be 150 min/week per 2008 Physical Activity Guidelines for Americans and American Heart Association recommendations, conducted in three 50 min sessions. The aerobic walking intervention will take place outdoors (e.g., trails, sidewalks, parks) or indoors (e.g., track in a local gym or a mall) depending on the preferences of the subject and weather. Session duration will be 20 min the first week and will be advanced by 5 min per week over 6 weeks.

Usual care with PD specific health education

Behavioral

In this study, patients will receive their usual medical treatment for motor and non-motor symptoms from their

primary neurologist. The investigators will use a streamlined form of PD specific health education prepared by the VA: My Parkinson's Story, which consists of a series of short videos prepared by the VA PADRECCs addressing various aspects of PD. These 6-12 minutes long videos are freely available on YouTube. The investigators can also provide them on a CD if subjects desire. They start with a patient testimony about the topic of the episode, followed by comments of experts in the field. The title of the episodes are: Early Parkinson's, Medications, Exercise, Memory, Visual Disturbances, Depression, Sleep, Speech and Swallowing, Impulsive Behaviors, Driving, Pain, Dyskinesias, Deep Brain Stimulation, Advanced Parkinson's Disease, Falls, The Caregiver, Hospitalization, Genetics, Environmental Exposure, Atypical Parkinsonism

Primary outcomes

  1. Change in MDS-UPDRS Part III Motor (OFF) Score

    Time frame: Final Visit at 1 year - Baseline

    Measures change in the severity of parkinsonism. Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Motor section (Part III), measured in the "practically defined" OFF state (after overnight, ~12 hours, withdrawal of PD medications). It measures specific signs like rigidity, tremor, bradykinesia (slowness of movement), and gait abnormalities by a certified rater. Each item is rated 0-4: 0 - Normal (no impairment), 1 - Slight, 2- Mild, 3 - Moderate, 4 - Severe. Total score is reported (range 0-132). Higher scores worse for individual data points. Lower value better for change score.

  2. Change in Flanker Task

    Time frame: Final visit at 1 year - Baseline

    Measures change in the executive function domains of inhibitory control and attention. Uncorrected Standard Score of the NIH Toolbox Flanker Inhibitory Control and Attention Test. The Raw Score is based on number correct × average reaction time (accuracy & speed composite). The Uncorrected Standard Score is based on age-normed raw score with mean = 100 and SD = 15. Score range 40-160 with interpretation below:

    ≥ 130 - Very Superior, 115-129 - Superior, 85-114 - Average, 70-84 - Below Average, < 70 - Impaired / markedly low attention control. Higher scores better for individual data points. Higher value better for change score.

  3. Change in Road Safety Error Count

    Time frame: Final Visit at 1 year - Baseline

    Number of safety errors made during an experimental real-world road drive test, scored by a certified driving instructor per criteria in the Iowa Department of Transportation's Drive Test Scoring Standards. Higher error count score worse. Lower scores better for change score.

  4. Change in the Parkinson's Disease Questionnaire-39 (PDQ-39) Score

    Time frame: Final Visit at 1 year - Baseline

    Questionnaire regarding activities of daily living and ability within the last month. PDQ-39 has 8 domains: Mobility (10 items) → max = 40, Activities of daily living (6 items) → max = 24, Emotional well-being (6 items) → max = 24, Stigma (4 items) → max = 16, Social support (3 items) → max = 12, Cognitions (4 items) → max = 16, Communication (3 items) → max = 12, Bodily discomfort (3 items) → max = 12. Domain Score=(Sum of item scores/Maximum possible)*100 . The main outcome measure is PDQ-39 Summary Index (PDQ-39 SI) is the mean of the 8 domain scores (range = 0 to 100). Higher scores at datapoints are worse. Lower change score is better.

  5. Change in Cingulum Cingulate Radial Diffusivity (rD)

    Time frame: Final Visit at 1 year - Baseline

    Brain tissue integrity. Change in regional diffusion coefficient for radial diffusivity (rD) on DTI. Higher scores worse at individual data points. Lower scores better for change.

  6. Change in Superior Longitudinal Fasciculus Radial Diffusivity (rD)

    Time frame: Final Visit at 1 year - Baseline

    Brain tissue integrity. Change in regional diffusion coefficient for radial diffusivity (rD) on DTI. Higher scores worse at individual data points. Lower scores better for change.

  7. Change in Putamen Radial Diffusivity

    Time frame: Final Visit at 1 year - Baseline

    Brain tissue integrity. Change in regional diffusion coefficient for radial diffusivity (rD) on DTI. Higher scores worse at individual data points. Lower scores better for change.

Secondary outcomes

  1. Change in MDS-UPDRS Non-motor Experiences of Daily Living Subscale (Part I) Score

    Time frame: Final Visit at 1 year - Baseline

    Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Non-Motor Experiences of Daily Living questionnaire (Part I). Part IA It measures complex behaviors (e.g., cognition, mood) by the rater based on patient/caregiver responses. Part IB asks patient/caregiver about various body functions. Each item is rated 0-4, and the score reflect the status of each item over the past week. Each item is rated 0-4: 0 - Normal (no impairment), 1 - Slight, 2- Mild, 3 - Moderate, 4 - Severe. Total score of IA and IB is reported (range 0-52). Higher scores at data points worse. Lower change scores better.

  2. Change in MDS-UPDRS Motor Experiences of Daily Living Score (Part II)

    Time frame: Final Visit at 1 year - Baseline

    Motor function. Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Motor Experiences of Daily Living questionnaire (Part II). It measures motor function based on patient/caregiver responses. Each item is rated 0-4, and the score reflect the status of each item over the past week. Each item is rated 0-4: 0 - Normal (no impairment), 1 - Slight, 2- Mild, 3 - Moderate, 4 - Severe. Total score is reported (range 0-52). Higher scores worse at individual datapoints. Lower change score better.

  3. Change in ON Period MDS-UPDRS Motor Examination Subscale Score (Part 3)

    Time frame: Final Visit at 1 year - Baseline

    Measures change in the severity of parkinsonism while antiparkinsonian medications are working. Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Motor section (Part III), measured in the ON state. It measures specific signs like rigidity, tremor, bradykinesia (slowness of movement), and gait abnormalities by a certified rater. Each item is rated 0-4: 0 - Normal (no impairment), 1 - Slight, 2- Mild, 3 - Moderate, 4 - Severe. Total score is reported (range 0-132). Higher scores worse for individual data points. Lower value better for change score.

  4. Change in MDS-UPDRS Dyskinesia and Motor Fluctuations (Part 4)

    Time frame: Final Visit at 1 year - Baseline

    Movement Disorder Society-Unified Parkinson's Disease Rating Scale, Motor Fluctuations and Dyskinesia questionnaire. It measures duration, severity, and functional impact of dyskinesias and OFF periods by questionnaire administered by a certified rater. Each item is rated 0-4: 0 - Normal (no impairment), 1 - Slight, 2- Mild, 3 - Moderate, 4 - Severe. Total score is reported (range 0-24). Higher scores worse at data points. Lower change score better.

  5. Change in Total MDS-UPDRS Score

    Time frame: Final Visit at 1 year - Baseline

    This is the simple addition of MDS-UPDRS Part I, II, and III (ON) total scores. This is a global measure of disease severity and encompasses motor and non-motor symptoms by subjective and objective measures. Higher scores at data points worse. Lower change scores better.

  6. Change in 2-Minute Walk Test

    Time frame: Final Visit at 1 year - Baseline

    Motor function. Locomotion, endurance. Distance that a participant can walk in 2-minutes at their usual speed, a measure in NIH Toolbox Motor Battery. It is measured in the ON state. Higher data point and change score better.

  7. Change in 9-Hole Peg Board Test (OFF)

    Time frame: Final Visit at 1 year - Baseline

    An assessment of fine motor dexterity. Participants are asked to place 9 pegs into a board with 9 holes, then remove them as quickly as possible, one hand at a time. Time to complete is reported. Part of NIH Toolbox Motor Battery. measured in the "practically defined" OFF state (after overnight, ~12 hours, withdrawal of PD medications). Higher time to complete is worse for individual data points. Lower value better for change score.

  8. Change in 9-Hole Peg Board Test of NIH Toolbox Motor Battery (ON)

    Time frame: Final Visit at 1 year - Baseline

    An assessment of fine motor dexterity. Participants are asked to place 9 pegs into a board with 9 holes, then remove them as quickly as possible, one hand at a time. Time to complete is reported. Part of NIH Toolbox Motor Battery. measured in the ON state (when antiparkinsonian medications are working).

    Higher time to complete is worse for individual data points. Lower value better for change score.

  9. Change in Montreal Cognitive Assessment (MOCA)

    Time frame: Final Visit at 1 year - Baseline

    This is a brief cognitive screening test that measures various domains. Range 0-30. A score of 26 or over is considered to be normal. Higher score at data points and for change better.

  10. Change in COGSTAT Score

    Time frame: Final Visit at 1 year - Baseline

    Composite measure of cognitive impairment (COGSTAT) by assigning standard T scores (mean=50, SD=10) to each of the seven tests from the neuropsychological assessment battery (COWA, CFT-Copy, CFT-Recall, AVLT-Recall, BVRT, BLOCKS, and TMT [B-A]). Higher scores better.

  11. Change in Controlled Oral Word Association Task (COWA)

    Time frame: Final Visit at 1 year - Baseline

    Number of words created for each letter (C, F, L) of the Controlled Oral Word Association Test over 60 seconds for each letter. A test of verbal fluency, probes executive function (initiation, self-monitoring, inhibition of repeats), language (lexical access, phonemic organization), attention and working memory domains. Average healthy adult produces 12-15 words per letter. Higher score at data points and change score better.

  12. Change in Block Design Test (BLOCKS)

    Time frame: Final Visit at 1 year - Baseline

    Total score of the completion of the Block Design test. This test evaluates the ability to analyze and synthesize abstract visual patterns, manipulate spatial information mentally, and coordinate visual-motor construction skills. Raw score is sum of all points based on accuracy and speed of reproducing 14 designs. (range=0-68) - higher score and change score better.

  13. Change in Judgment of Line Orientation Test (JLO)

    Time frame: Final Visit at 1 year - Baseline

    Judgement of Line Orientation test measures ability to perceive and match the angular relationships between line orientations. It is a visuospatial perception test. Raw score is sum of all correctly identified items (range 0-30). Higher score at data points and change score better.

  14. Change in Delayed Recall of Rey Auditory Verbal Learning Test (AVLT-Recall)

    Time frame: Final Visit at 1 year - Baseline

    Cognition. Memory. Number of words that can be recalled after at least 30-minutes after hearing the list. Higher scores at data points and change scores better.

  15. Change in Complex Figure Test -Copy (CFT-Copy)

    Time frame: Final Visit at 1 year - Baseline

    Ability to copy the Rey-Osterrieth Complex Figure. Measures visuospatial construction, perceptual organization, planning, and motor control. There are 18 distinct elements, each scored 0-2, with a range of total score 0-36. Higher score at data points and change score better.

  16. Change in Complex Figure Test-Recall (CFT-Recall)

    Time frame: Final Visit at 1 year - Baseline

    Ability to remember and draw the Rey-Osterrieth Complex Figure as accurately as possible after 30 minutes of copying it. It measures long-term visual memory and retention. There are 18 distinct elements, each scored 0-2, with a range of total score 0-36. Higher score at data points and change score better.

  17. Change in Benton Visual Retention Test (BVRT)

    Time frame: Final Visit at 1-year - Baseline

    Test of visuospatial perception and memory. 10 geometric designs are shown to the participant. Each design is viewed for 10 seconds and then reproduced from memory. We are reporting error counts (range 0-10). Higher scores worse at data points. Lower change value better.

  18. Change in Trail Making Test- A (TMT-A)

    Time frame: Final Visit at 1 year - Baseline

    Test of processing speed, visual scanning. Time in seconds to connect numbers in ascending order. Higher time at data points worse. Lower change value better.

  19. Change in Trail Making Test - B (TMT-B)

    Time frame: Final visit at 1-year - Baseline

    Test of set-shifting, executive function, divided attention. Time to connect letters and numbers, alternating between numbers and letters, going in ascending order. Higher time worse. Lower change value better.

  20. Trail Making Test B-A (TMT B-A)

    Time frame: Final Visit at 1-year - Baseline

    Measure of executive control from motor speed. Calculated as (Trail Making Test B - Trail Making Test A). Higher scores at data points worse. Lower change scores better.

  21. Change of Geriatric Depression Scale (GDS) Score

    Time frame: Final Visit at 1 year - Baseline

    Severity of depression. Higher scores worse. Range: 0-15

  22. Change in Beck Anxiety Inventory (BAI) Score

    Time frame: Final Visit at 1 year - Baseline

    anxiety symptoms within the last week. 21-item self-report questionnaire each describing a common anxiety symptom (physical or cognitive). Item scores: 0 - Not at all, 1 - Mildly-it did not bother me much, 2 - Moderately-it was very unpleasant but I could bear it, 3 - Severely-I could barely stand it. Range 0-63. Higher scores worse at data points. Lower change value better.

  23. Change in Fatigue Severity Scale (FSS)

    Time frame: Final Visit at 1 year - Baseline

    Severity of fatigue. questions on symptoms of fatigue within the last week. Format: 9 statements such as "I am easily fatigued" rated on a 7-point Likert scale (1 = strongly disagree, 7 = strongly agree).

    Total score = sum of all items / number of items answered (i.e., average of 9 items). Range: 1 - 7. Interpretation: 1-2=No or minimal fatigue, 3-4=Moderate fatigue, ≥ 5: Severe fatigue (commonly used clinical cutoff). Higher scores worse at data points. Lower change score better.

Other outcomes

  1. Change in VO2max on Cycle Ergometry

    Time frame: Final Visit at 1-year - Baseline

    Measurement of aerobic fitness in the ON stage. VO2 max is the maximum amount of oxygen the body can use during intense exercise, serving as a key indicator of cardiovascular fitness and endurance. It is measured in milliliters of oxygen per kilogram of body weight per minute (mL/kg/min). Higher scores at data points and change score better.

  2. Change in L-dopa Equivalent Daily Dose (LEDD)

    Time frame: Final visit at 1-year - Baseline

    LEDD is a standardized measure used to compare the total dopaminergic medication load across different Parkinson's disease (PD) treatments. It converts various dopaminergic agents to a common reference - the amount equivalent to 100 mg of standard oral levodopa - allowing consistent comparison across studies and patients. Higher is worse at data points. Lower change value better.

Sponsors and collaborators

Lead sponsor

VA Office of Research and Development

Fed

Collaborators

  • University of Iowa

Registry information

Official study title

Long Term Aerobic Exercise to Slow Progression in Parkinson's Disease

Acronym: LTAE-PD

Important dates

Study start
2019
Primary completion
2024
Study completion
2024
First posted
Jan 17, 2019
Registry last updated
Mar 12, 2026

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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