Intensity of Aerobic Training and Neuroprotection in Parkinson's Disease

Study Overview
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Brief Summary
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In phenotypic animal models of Parkinson's Disease (PD), chronic physical exercise has produced nigrostriatal neuroprotection and symptom improvement, provided training was of high-intensity and prolonged duration (>3 months in rodent models). Conventional physical therapy in Parkinson's disease (PD) has traditionally avoided fatigue and high intensity workouts. Yet, in PD controlled studies have shown that: (i) an acute aerobic stress produces endogenous dopamine immediately after the exercise and (ii) short term (a few weeks) high intensity aerobic training enhances D2 striatal receptor density and cortical excitability and clinically improves walking, upper limb and executive functions; (iii) long-term (six months) high intensity aerobic treadmill training is associated with less deterioration of subjective UPDRS III score compared to a waiting list. Long-term high intensity aerobic training has not been compared to low or medium intensity training in PD patients for its objective motor, cognitive and putative neuroprotective effects.

Detailed Description
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A short description, 5000 characters Intro: In phenotypic animal models of Parkinson's Disease (PD), chronic physical exercise has produced nigrostriatal neuroprotection and symptom improvement, provided training was of high-intensity and prolonged duration (>3 months in rodent models). Conventional physical therapy in Parkinson's disease (PD) has traditionally avoided fatigue and high intensity workouts. Yet, in PD controlled studies have shown that: (i) an acute aerobic stress produces endogenous dopamine immediately after the exercise and (ii) short term (a few weeks) high intensity aerobic training enhances D2 striatal receptor density and cortical excitability and clinically improves walking, upper limb and executive functions; (iii) long-term (six months) high intensity aerobic treadmill training is associated with less deterioration of subjective UPDRS III score compared to a waiting list. Long-term high intensity aerobic training has not been compared to low or medium intensity training in PD patients for its objective motor, cognitive and putative neuroprotective effects. Hypothesis/Objective Hypothesis High-intensity aerobic exercises practiced over 9 months will produce greater symptomatic motor and cognitive benefits and neuroprotective effects in PD patients, than low or medium intensity training. Primary Objective To compare the motor effects of a 9-month conventional physical therapy program (light aerobic exercises), an aerobic program of medium intensity on stationary bicycle (50% maximal oxygen uptake, VO2 max), and an aerobic program of high intensity (70% VO2 max) in Parkinson's disease. Secondary Objectives To evaluate aerobic capacities before and after the program. To evaluate cognitive functions, depression, quality of life before and after each program as well as 3 months following program termination and motor function 3 months following program termination. To explore potential neuroprotective effects of a 9-month aerobic program through specialized brain imaging (123I-Ioflupane SPECT) and a potential aerobic intensity-effect of such neuroprotection. Primary outcome measure Change in MDS-UPDRS III Score (Movement Disorders Society - Unified Parkinson's Disease Rating Scale) in the  OFF  state between Day 1 and Month 9. Secondary outcome measures OFF-state at Day 1, Month 9, Month 12 Two-minute walking test from D1 to M9 Modified 20-meter up-and-go test (AT20) 2-minute walk test (from M1 to M12) Global Mobility Task (GMT) scale (standing up off the floor) Upper limb performance in activities of daily living (Mount Sinai Parkinsonism Impairment Rating Scale, MSPIR) Static posturography Maximal aerobic capacity (VO2 max) Montreal Cognitive Assessment test (MoCA) Digit span task (forward and backward) Trail Making Test ON-state at D1, M9, M12 MDS-UPDRS III Score; Mean number of steps performed over the past three weeks (pedometry); Monthly incidence of falls in the past 3 months (questionnaire) Daily consumption of dopaminergic medications Quality of life (EQ-5D) Depression (GDS15) Dopaminergic striatal function by SPECT [123I] beta-CIT striatal uptake at D1, M12. Method Design Single-blind randomized study, 3 parallel groups (n= 7 or 8 per group and per center, over 3 centers): Group 1  High Intensity Aerobic exercise , HIA (70% VO2 max); Group 2  Medium Intensity Aerobic exercise , MIA (50% VO2 max); Group 3  Conventional Physical Therapy , CPT HIA and MIA groups are experimental groups and CPT group is the control group. Each group will attend 3 weekly 45-minute sessions at the hospital for 9 months. Number of subjects needed: 69 Inclusion criteria Patients with diagnosis of PD according to the UKPDSBB criteria to distinguish idiopathic PD from atypical parkinsonism such as multi-system atrophy, progressive supra-nuclear paralysis or vascular parkinsonism; Previous MRI available, to further help distinguish idiopathic PD from atypical parkinsonism; Hoehn & Yahr Stage 1-3 in OFF state; Age > 18; Signed informed consent to participate in study. Non-inclusion criteria Patients lacking motivation or ability to participate in training sessions for 9 months, in the investigator's opinion; contra-indications to high-intensity aerobic training in the cardiologist's opinion; contra-indications to perchlorate de potassium or to the use of 123I-FP-CIT; concurrent severe co-morbidities; cognitive deficit limiting participation to the program; Montreal Cognitive Assessment test (MoCA)<23; uninsured patient; participation in another ongoing interventional clinical trial (drug therapy, surgical treatment, another rehabilitation treatment, medical device); Pregnancy or current lactation, or no efficacious contraception during the 9 months of intervention. Recruitment period: 1 year; Study duration: 26 months (24 patients recruited in 2 centers and 21 patients in the other 2 centers) Participation duration for each patient: 14 months Number of participating centers: 3

Official Title
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Neuroprotective, Motor and Cognitive Impact of a Long-standing Aerobic Training Program in Parkinson's Disease. A Multicenter Comparison of the Effects of Two Aerobic Programs of Graded Intensities and a Conventional Physical Therapy Program Prolonged for 9 Months on Nigrostriatal, Motor and Cognitive Functions.

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Behavioral: High Intensity Aerobic program
* Other: Conventional Physical Therapy
* Behavioral: Medium Intensity Aerobic program


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of PD according to the UKPDSBB criteria Previous MRI available, to further help distinguish idiopathic PD from atypical parkinsonism Hoehn & Yahr Stage 1-3 in OFF state Age > 18 Signed informed consent to participate in study Exclusion Criteria: Patients lacking motivation or ability to participate in training sessions for 9 months, in the investigator's opinion Contra-indications to high-intensity aerobic training in the cardiologist's opinion Contra-indications to perchlorate de potassium or to the use of 123I-FP-CIT Concurrent severe co-morbidities Cognitive deficit limiting participation to the program in the investigator's opinion Montreal Cognitive Assessment test (MoCA)<23 Uninsured patient Participation in another ongoing interventional clinical trial (drug therapy, surgical treatment, another rehabilitation treatment, medical device) Pregnancy or current lactation, or no efficacious contraception during the 9 months of intervention.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Single-blind randomized study, three parallel groups (n= 7 or 8 per group and per center, over 3 centers): Group 1 Conventional Physical Therapy, CPT Group 2 Medium Intensity Aerobic program, MIA (50% VO2 max); Group 3 High Intensity Aerobic program, HIA (70% VO2 max); HIA and MIA groups are experimental groups and CPT group is the control group. Each group will attend 3 weekly 45-minute sessions at the hospital for 9 months.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Conventional Physical Therapy<br>Three sessions a week of hospital-based conventional physical therapy, all in presence and with the guidance of a registered physical therapist, for nine months | Other: Conventional Physical Therapy<br>* Three sessions a week of hospital-based exercise on a stationary bicycle, all in presence and with the guidance of a physical education teacher, for nine months<br>|
| Sham Comparator: Medium Intensity Aerobic exercise (50% VO2 max)<br>Three sessions a week of hospital-based Medium Intensity Aerobic exercise (50% VO2 max); on a stationary bicycle, all in presence and with the guidance of a physical education teacher, for nine months | Behavioral: Medium Intensity Aerobic program<br>* Three sessions a week of hospital-based exercise on a stationary bicycle, all in presence and with the guidance of a physical education teacher, for nine months<br>|
| Experimental: High Intensity Aerobic exercise<br>Three sessions a week of hospital-based High Intensity Aerobic exercise (70% VO2 max) on a stationary bicycle, all in presence and with the guidance of a physical education teacher, for nine months | Behavioral: High Intensity Aerobic program<br>* Three sessions a week of hospital-based exercise on a stationary bicycle, all in presence and with the guidance of a physical education teacher, for nine months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in MDS-UPDRS III Score (Movement Disorders Society - Unified Parkinson's Disease Rating Scale) in the  OFF  state between Day 1 and Month 9. | The MDS-UPDRS III Score is a subjective assessment of motor symptoms based on the addition of ordinal 1-4 scores. | at day 1 and 9 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Two-minute walking test at maximal speed |  | at day 1, 9 Months and 12 Months | 
| Modified 20-meter up-and-go test (AT20) |  | at day 1, 9 Months and 12 Months | 
| Global Mobility Task (GMT) | time required to stand up off the floor | at day 1, 9 Months and 12 Months | 
| Upper limb performance in activities of daily living (Mount Sinai Parkinsonism Impairment Rating Scale, MSPIR) | three unimanual tasks on each side and six bimanual everyday living tasks all times | at day 1, 9 Months and 12 Months | 
| Maximal aerobic capacity (VO2 max) |  | at day 1, 9 Months and 12 Months | 
| Montreal Cognitive Assessment test (MoCA) |  | at day 1, 9 Months and 12 Months | 
| Digit span task (forward and backward) |  | at day 1, 9 Months and 12 Months | 
| Trail Making Test |  | at day 1, 9 Months and 12 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson's disease, Aerobic Exercises, High Intensity Training, Neuroprotection