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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
57
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.
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
University of Iowa Hospitals & Clinics
Iowa City, Iowa, United States
Iowa City VA Health Care System, Iowa City, IA
Iowa City, Iowa, United States
Change in MDS-UPDRS Part III Motor (OFF) Score
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.
Time frame: Final Visit at 1 year - Baseline
Change in Flanker Task
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.
Time frame: Final visit at 1 year - Baseline
Change in Road Safety Error Count
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.
Time frame: Final Visit at 1 year - Baseline
Change in the Parkinson's Disease Questionnaire-39 (PDQ-39) Score
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.
Time frame: Final Visit at 1 year - Baseline
Change in Cingulum Cingulate Radial Diffusivity (rD)
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.
Time frame: Final Visit at 1 year - Baseline
Change in Superior Longitudinal Fasciculus Radial Diffusivity (rD)
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.
Time frame: Final Visit at 1 year - Baseline
Change in Putamen Radial Diffusivity
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.
Time frame: Final Visit at 1 year - Baseline
Change in MDS-UPDRS Non-motor Experiences of Daily Living Subscale (Part I) Score
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.
Time frame: Final Visit at 1 year - Baseline
Change in MDS-UPDRS Motor Experiences of Daily Living Score (Part II)
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.
Time frame: Final Visit at 1 year - Baseline
Change in ON Period MDS-UPDRS Motor Examination Subscale Score (Part 3)
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.
Time frame: Final Visit at 1 year - Baseline
Change in MDS-UPDRS Dyskinesia and Motor Fluctuations (Part 4)
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.
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Time frame: Final Visit at 1 year - Baseline
Change in Total MDS-UPDRS Score
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.
Time frame: Final Visit at 1 year - Baseline
Change in 2-Minute Walk Test
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.
Time frame: Final Visit at 1 year - Baseline
Change in 9-Hole Peg Board Test (OFF)
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.
Time frame: Final Visit at 1 year - Baseline
Change in 9-Hole Peg Board Test of NIH Toolbox Motor Battery (ON)
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.
Time frame: Final Visit at 1 year - Baseline
Change in Montreal Cognitive Assessment (MOCA)
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.
Time frame: Final Visit at 1 year - Baseline
Change in COGSTAT Score
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.
Time frame: Final Visit at 1 year - Baseline
Change in Controlled Oral Word Association Task (COWA)
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.
Time frame: Final Visit at 1 year - Baseline
Change in Block Design Test (BLOCKS)
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.
Time frame: Final Visit at 1 year - Baseline
Change in Judgment of Line Orientation Test (JLO)
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.
Time frame: Final Visit at 1 year - Baseline
Change in Delayed Recall of Rey Auditory Verbal Learning Test (AVLT-Recall)
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.
Time frame: Final Visit at 1 year - Baseline
Change in Complex Figure Test -Copy (CFT-Copy)
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.
Time frame: Final Visit at 1 year - Baseline
Change in Complex Figure Test-Recall (CFT-Recall)
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.
Time frame: Final Visit at 1 year - Baseline
Change in Benton Visual Retention Test (BVRT)
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.
Time frame: Final Visit at 1-year - Baseline
Change in Trail Making Test- A (TMT-A)
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.
Time frame: Final Visit at 1 year - Baseline
Change in Trail Making Test - B (TMT-B)
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.
Time frame: Final visit at 1-year - Baseline
Trail Making Test B-A (TMT B-A)
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.
Time frame: Final Visit at 1-year - Baseline
Change of Geriatric Depression Scale (GDS) Score
Severity of depression. Higher scores worse. Range: 0-15
Time frame: Final Visit at 1 year - Baseline
Change in Beck Anxiety Inventory (BAI) Score
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.
Time frame: Final Visit at 1 year - Baseline
Change in Fatigue Severity Scale (FSS)
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.
Time frame: Final Visit at 1 year - Baseline