High Intensity Aerobic Exercise Enhances Function in Parkinson s disease

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1 % DA loss In putamen Disclosures High Intensity Aerobic Exercise Enhances Function in Parkinson s disease JLA has authored intellectual property associated with the forced exercise bike and ipad modules. ABR has nothing to disclose. Jay L. Alberts, Ph.D. Cleveland Clinic albertj@ccf.org Anson Rosenfeldt, PT, DPT, NCS, MBA Cleveland Clinic rosenfa2@ccf.org APTA Combined Sections Meeting February 23, 2018 Course Objectives At the end of the presentation, the participant will: Describe the potential mechanism underlying high intensity aerobic exercise in individuals with PD. Discuss the motor and non-motor outcomes following a forced exercise paradigm in individuals with PD. Discuss the clinical translation of a forced exercise paradigm to for individuals with PD. Discuss the application of forced-exercise in the management of stroke. Understand the value of using objective measures of cognitive and motor function to compliment clinical measures of motor and non-motor function. Course Outline I. Current medical management of patients with PD II. Rationale for the use of forced-exercise in animal models of PD III. Description of forced-exercise intervention for patients with PD IV. The global motor and non-motor impact of forcedexercise in patients with PD results from our clinical trials V. Forced exercise in Stroke VI. Question and Answer Introduction Role of basal ganglia in motor control The primary cause of PD is loss of dopamine projections to the basal ganglia. Degeneration of dopamine containing neurons in the substantia nigra pars compacta (SNc) Pre-clinical 0% phase 100% Symptom onset Age (years) 1

2 Levadopa Dose Therapeutic Window Dyskinesia Years Therapeutic d Window Bradykinesia Therapeutic window narrows with advancing disease Difficult to produce symptom relief without side effects Surgical therapies are available for late stage PD Therapies Pharmacological L-DOPA DA agonists MAO inhibitor Glutamate antagonists Surgical Pallidotomy Deep Brain Stimulation STN GPi Physical, occupational, speech therapies Needed: Neuroprotection A neuroprotective therapy is the single most important unmet medical need in Parkinson s disease (Olanow et al., 2008) Adapted from Sage and Mark, Neurology 1992 Who is being referred to therapy services? Nijkrake 2008 (Netherlands) Survey of 216 PD patients % of patients utilizing service Physical Therapy 62.5 Occupational Therapy 8.5 Speech Therapy % reported a fall in the past year 33% received PT Rehabilitation Models of PD High amplitude, high velocity movements Strategies to reduce freezing, improve spatiotemporal aspects of gait (step length, cadence, velocity, etc.) Auditory cuing/metronome/music: external rhythm compensates for defective internal rhythm of the basal ganglia Visual cuing: motor planning deficit, no longer an automatic, rhythmic task that is processed through the basal ganglia Wu 2013 Rehabilitation Models of PD Compensation vs. Neuroplasticity using cerebello-thalmo-cortical circuit to bypass the defective basal ganglia What can animal models tell us about forced exercise and neuroplasticity in PD? Wu 2005,

3 Forced exercise and neuroprotection in rodent models of PD Forced exercise and neuroprotection in rodent models of PD Tajiri 2010 Fisher 2004 Effects of Forced-Exercise in Animal Models of PD From the Cornfields to a Clinical Trial to Clinical Practice Increased release of dopamine Decreased synaptic clearance of dopamine Increase in dopamine D2 receptor Increase in neurotrophic factors (BDNF, GDNF, IGF-1) Greater intensity (forced-exercise) results in higher levels of neurotrophic factors and more extensive the anatomical regions involved Present FE is neuroprotective and improves motor function. Pie or Pedaling??? Closing the gap between animal and human studies 3

4 Estimated V02 max (ml/kg/min) UPDRS Motor III Score Closing the gap between animal and human studies On DBS Off DBS Patient A Start Target 1 End On DBS Off DBS Patient B What is forced-exercise for PD patients? Voluntary efforts of the patient are augmented Exercise rate increased Consistent pedaling rate at high RPMs Consistent pedaling pattern Aerobic 65-80% target HR zone Participant is not passive 15 Off DBS (4 hrs) + forced-exercise Off DBS (4 hrs) + no exercise X Position (cm) Proposed Forced-Exercise Mechanisms of Action Rationale for Forced-Exercise in PD Decreased activation in cortical areas Impaired sensory-motor integration Degraded quantity and quality of sensory info. Exercise rate is important (animal studies) Augment, not replace, voluntary efforts (robotic studies) Increase quantity and quality of afferent info. Hypothesis: Forced, not voluntary, exercise will result in global motor improvements in PD patients. Forced vs. Voluntary Exercise Forced Exercise (FE) Three sessions/wk for 8 weeks 5-10 min warm up, 40 min main set, 5-10 min cool down 60-80% target HR FE group pedaled 30% faster compared to the VE group Voluntary Exercise (VE) Three sessions/wk for 8 weeks 5-10 min warm up, 40 min main set, 5-10 min cool down 60-80% target HR Aerobic exercise improves fitness, only FE improves clinical ratings Baseline Forced Voluntary Baseline Mid % -28% -5% 4

5 High intensity exercise improves UE motor function 1996 Study enrollment Post High Intensity Exercise Induces CNS Changes Measured with fmri N=38 individuals with PD Forced or Voluntary rate cycling (n=23) Non-exercise control (n=15) 8 week cycling intervention Study design 10 PD patients Three conditions: 1. No meds 2. Meds 3. No meds + FE - 40 min of FE (80-90 RPMs) Motor, CNS improvements appear to be related to cycling intensity Colors represent change in functional connectivity from baseline to that is related to cadence. Greater increase in connectivity between thalamus and motor cortex in those who cycled faster Cyclical Lower-extremity Exercise (CYCLE) Trial 5

6 From Tandem to Automation Study Overview Screening & Consent Baseline Biking Stress Test (N=100) Baseline Testing On-Medication Off-Medication 3x/wk for 8 wks FE (N=40) VE (N=40) End of Treatment () Testing Off-Medication Noexercise Control (N=20) + 4 weeks Off-Medication + 8 weeks Off-Medication Participant screening Inclusion Criteria Clinical diagnosis of idiopathic PD Age between years Hoehn & Yahr stage II-III when on-medication Not currently engaged in formal PD-specific exercise intervention or clinical study Exclusion Criteria Existing cardiopulmonary disease or stroke (ACSM screening criteria) Dementia Other medical or musculoskeletal contraindications to exercise Cardiopulmonary Stress Test (CPX) Upright stationary bike Increasing workload by 25W every two minutes until 100W, then increase by 50W until termination Continuous 12-lead EKG to monitor for cardiac abnormalities Gas analysis to determine peak VO2 99% of participants were cleared to exercise CYCLE Trial Consort Diagram CYCLE Trial Demographics Factor FE (N = 40) VE (N = 39) Control (N = 20) Male 23 (57) 21 (54) 14 (70) Age (years) 63 ± 8 61 ± 9 65 ± 6 Disease duration (years) 4 [1, 4] 3 [2, 6] 3 [1, 4] Levodopa dosage (mg) 475 [300, 600] 500 [306, 690] 450 [145, 562] Years of education 16 ± 3 16 ± 3 17 ± 2 Race White 38 (95) 38 (97) 19 (95) Black 1 (2) 1 (3) 0 (0) Asian 1 (2) 0 (0) 1 (5) Hispanic ethnicity 1 (2) 0 (0) 0 (0) UPDRS (off meds) 38 ± ± ± 12 Hoehn & Yahr II (off meds) 30 (75) 28 (72) 14 (70) FE = forced exercise; VE = voluntary exercise. Summary statistics presented as mean ± standard deviation (normally distributed characteristics), median [first quartile, third quartile] (characteristics with skewed data), or N (%) (categorical data). Groups were not significantly different from each other (p>0.25) 6

7 CYCLE Trial Training Example Individuals were able to maintain exercise intensity Exercise characteristics Exercise Attendance (out of 24 sessions) FE (N = 36) VE (N = 36) 97% 92% HRR % 66% [60%, 70%] 69% [64%, 79%] Average heart rate (bpm) 111 ± ± 14 Average cadence (rpms) 79 ± ± 15 Example of HR training data from one exercise session and time spent in target HR range Average power (W) 34 [21, 56] 41 [35, 64] Summary characteristics are mean ± SD, median [Q1, Q3], or N (%). Both FE and VE exercised 3x/wk for 8 weeks; 60-80% of HRR Aerobic exercise increases CV fitness Cardiovascular Outcomes Maximal and submaximal VO2 increase for FE and VE, not control Relationship Between Cadence, Peak VO2 Primary Clinical Motor Outcome At 60 rpms and greater, there is a linear relationship between peak VO2 and rpms As rpms increase, peak VO2 increases 7

8 MDS-Unified Parkinson s disease Rating Scale (UPDRS) Motor High intensity exercise improves motor symptoms Rates global motor symptoms of PD Based on the 4 cardinal motor symptoms (rigidity, bradykinesia, tremor, gait/posture) Subjective 0-4 rating 0 = no symptoms 4 = most severe High intensity exercise improves motor symptoms Does MDS-UPDRS III change from baseline (off medication) to? Do the slopes differ by exercise group? High intensity exercise improves motor symptoms Group trajectories significantly differ over time. + FE and VE groups decrease significantly more compared to Controls. + Is there a significant difference between groups on mean MD- UPDRS III at? Mean (95% CI) MDS-UPDRS III by exercise group over time. Mean MDS-UPDRS III scores are significantly higher at among FE and VE patients compared to Controls. Mean (95% CI) MDS-UPDRS III by exercise group over time. Medication and high intensity exercise have similar effects on motor symptoms Does MDS-UPDRS III change from baseline (on medication) to? Does MDS-UPDRS III change from baseline (on medication) to baseline (off medication)? Medication and high intensity exercise have similar effects on motor symptoms Group trajectories differ over time. FE and VE scores increased significantly when they were tested off medication. + Do the slopes differ by exercise group? Is there a significant difference between groups on mean MD- UPDRS III at? Mean (95% CI) MDS-UPDRS III by exercise group over time. + No evidence that baseline scores on medication differed from scores. Mean (95% CI) MDS-UPDRS III by exercise group over time. 8

9 Overall motor symptoms results Secondary Outcomes Functional Mobility Functional mobility analysis To characterize exercise prescription on PDrelated functional mobility Evaluate exercise modality by comparing the 2 types of aerobic exercise FE (n=30) VE (n=30) Individuals with PD experience mobility dysfunction Up to 87% of individuals exhibit gait dysfunction in the early stages of diagnosis 35-90% will experience at least one fall/year In PD, 80% of falls occur in the home when individuals are performing daily activities such as walking, standing, and transferring Turning increases the risk for falls due to postural control impairments with weight shifting, asymmetry of producing different step lengths, and freezing The Timed Up and Go (TUG) is a quick and simple mobility assessment itug can discriminate between functional tasks itug Data from IMU Sensor in ipad 9

10 Overall mobility improves following aerobic exercise Overall mobility improves in VE but not FE 8.8 3% Total Trial Times (sec) % 7.6 Baseline On Baseline Off +8 Evaluation Significant difference from Baseline Off Significant difference from Baseline On Significant difference from Baseline Off Significant difference from Baseline On Gait Speed Increase in VE, but not FE Turning velocity is faster in both FE and VE 3% 6% 3% Significant difference from Baseline Off Significant difference from Baseline On Significant difference from Baseline Off Significant difference from Baseline On Improvements in mobility Improvements in mobility VE Improvements in turning, gait speed FE Improvements in gait speed Exercise characteristics FE (N = 36) VE (N = 36) HRR % 66% [60%, 70%] 69% [64%, 79%] Improvements are due to increased acceleration and amplitude of movement following exercise Reduction in bradykinesia NJS ML (m) % Baseline On Baseline Off +8 Evaluation Average heart rate (bpm) Average cadence (rpms) 111 ± ± ± ± 15 Average power (W) 34 [21, 56] 41 [35, 64] Summary characteristics are mean ± SD, median [Q1, Q3], or N (%). Significant difference from Baseline Off Significant difference from Baseline On 10

11 Secondary Outcomes Gait Assessment Baseline Testing Gait Assessment PD exercise intervention N = 15 N=1 worsening health status PD control (no exercise) N = 15 N=1 worsening health status Healthy Older Adults N = 15 N=1 removed after matching Final Analysis N = 14 N = 14 N = 14 Biomechanical Gait Analysis High Intensity Cycling Improves Gait Baseline Subject BG_026 VE group Right side affected Single-Task condition High intensity exercise elicits increase in arm swing Baseline Subject BG_014 VE group Left side affected Single-Task condition 56.6% Increase High intensity exercise elicits increase in gait speed PD exercisers 1.8 PDE - Walking Speed 1.8 PD non-exercisers PDC - Walking Speed Speed (m/s) (0.86) (1.00) Speed (m/s) (0.91) (0.80) 10.1% Increase Baseline 0.0 Baseline 11

12 High intensity exercise normalized gait speed Velocity was not significantly different from healthy controls post intervention High intensity exercise normalized stance phase & step length Spatiotemporal variables were not significantly different from healthy controls post intervention 2.0 Velocity Gait Speed HC (25%~75%) PDE (25%~75%) Range within 1.5IQR Median Line Stance Phase HC (25%~75%) PDE (25%~75%) Range within 1.5IQR Median Line 100 Step Length HC (25%~75%) PDE (25%~75%) Range within 1.5IQR Median Line m/s % gait cycle % leg length HC PDE HC PDE 0 HC PDE HC PDE Baseline Baseline 0.0 HC PDE HC PDE Baseline Stance Phase Step Length Relationship between PD and depression Secondary Outcomes - Quality of Life 40-50% of individuals with PD will experience depression Aerobic exercise is effective in treating depression in those without PD Less is known about aerobic exercise, PD, and depression High intensity exercise may improve depression symptomology Can FE be used to enhance Recovery of Function after Stroke? Exercise (n=72) Control (n=19) Percent change pre to post: 8% improvement 15% worsening Participants with mild-severe depressive symptomology at baseline: 15 1 Participants who improved depression categories: 7 0 Participants who worsened depression categories:

13 Applying high intensity exercise to individuals with stroke Aerobic Exercise + Task Practice promotes recovery in rodent models of stroke Hypothesis: Aerobic exercise will influence motor recovery and non-motor function in individuals with stroke Anticipated Outcome: Those in the FE group will have a greater recovery of motor and non-motor function than VE and RTP alone Ploughman 2007 Proposed Mechanism of FE after Stroke Study Overview Screening & Consent Baseline Biking Stress Test Baseline Testing 3x/wk for 8 wks FE + RTP VE + RTP RTP Only End of Treatment () Testing Biking Stress Test + 4 weeks Inclusion/Exclusion Criteria Inclusion years old >6 months post ischemic stroke Approval from physician to participate in stress test on Fugl-Meyer upper extremity motor assessment Ability to follow 1-2 step commands Exclusion Cardiac or pulmonary contraindication to exercise (cardiomyopathy, PE, afib, MI, etc.) Other musculoskeletal contraindications to exercise Major psychiatric disorder Anti-spasticity injections (botox) within the past 3 months Uncontrolled BP BASELINE End of treatment () FE + RTP (n=6) FE + RTP (n=6) N=1 Recurrent Stroke N=1 Dropout N=1 Received Botox Screened (n=147) Randomization (n=20) VE + RTP (n=8) VE + RTP (n=6) N=1 Dropout RTP (n=6) RTP (n=5) + 4 FE + RTP (n=5) VE + RTP (n=6) RTP (n=5) 13

14 Participant Demographics Three Time-Matched Intervention Groups Intervention Intensity Intervention FE + RTP % HRR VE + RTP 60-80% HRR RTP only 45 min 45 min Repetitive Task Practice (RTP) Focus on maximizing reps Selected 3-5 tasks/session reps of each task Type of practice ACTIVE Incorporate ROM into functional activity Blocked, target/goal-oriented, specificity of training Standing vs. Sitting Minimize rest time Grading of activities RTP with varying levels of UE function Impairment/Functional Limitation Lower functioning UE Decreased shoulder AROM and strength making donning a coat difficult Higher functioning UE Impaired intrinsic hand coordination limiting writing legibility Decreased shoulder ER resulting in difficulty washing hair Task Using gross motor shoulder flex/abd to knock down dominos dispersed on tray table Writing practice on a lined white board Overhead throwing to target with emphasis on external rotation during wind-up Grading of Task Move domino location on table Changing the size of the lines to vary letter size requirements Varying the distance of the target Representative Day of HR Data RTP Videos 14

15 Individuals achieved AHA/ASA recommendations for aerobic exercise Peak VO2 Cardiovascular Outcomes 80 VE+RTP FE+RTP Percentage of HRR (%) AHA/ASA AE Guidelines 0 VE-02 VE-06 VE-07 VE-14 VE-17 VE-21 FE-03 FE-05 FE-08 FE-13 FE-18 FE-22 individual on beta blockers Subjects High intensity exercise improves cardiovascular fitness Mean Peak VO2 Motor Outcomes Baseline Timepoint RTP VE FE The RTP group performed 60% more reps High intensity exercise improves gross motor function NS FE 25 NS Avg. Number of Repetitions/Session NS VE RTP Change in Fugl-Meyer Score (points) NS NS FE+RTP VE+RTP RTP only MCID 0 FE VE RTP 0 Baseline to Baseline to +4 Group p <.05 Time Points 15

16 Normalized Score Normalized Score Secondary Outcome Non-Motor Quality of Life Outcome Analysis A second study with identical aerobic exercise groups was completed Additional patients completed the intervention Comparison with a control group who completed stroke education sessions + RTP FE+RTP (n=16) VE+RTP (n=16) EDU+RTP (n=8) Depression and Stroke Aerobic exercise improved QOL Rehabilitation following stroke aims not only to improve physical limitations, but also to restore QOL Approximately 1 in 3 survivors of stroke develop post-stroke depression (PSD) PSD is associated with increased disability, lower QOL, and higher mortality Benefits of aerobic exercise on depression in individuals without stroke Stroke Impact Scale - Hand Function Stroke Impact Scale - Strength Forced exercise improved cognitive composite Further investigation into aerobic exercise and depression 16

17 Recommended Screening for PD Clinical Implementation Screening Tool Utilized: Pre-Participation for Exercise Questionnaire (American College of Sports Medicine) 100 patients enrolled 94 cleared from initial metabolic stress test 5 underwent follow-up testing and obtained clearance 1 chose not to follow-up (could not proceed) Do all patients need a formal stress test after stroke? AHA/ASA recommend that individuals with stroke undergo a graded exercise test with EKG. If the physician overseeing the patient s care determines an exercise test is not indicated or such an assessment in a given facility is not possible, the initiation of an exercise training program, individually tailored to a patient s physical capabilities, should not be delayed. In lieu of graded maximal exercise tests, submaximal tests may be considered for stroke survivors. 6MWT What other equipment can be used for FE? Billinger, et al., Physical Activity and Exercise Recommendations for Stroke Survivors: A Statement for Healthcare Professionals From the AHA/ASA. Stroke Eliminating barriers to cycling intervention Clinical Translation Keeping feet on pedals PD: Rigidity, dystonia, dyskinesia Stroke: Hyper/ hypotonic, altered sensation and proprioception Clip in biking shoe Theraband for pedals, hip abduction Warm up time Baseline deconditioning 10 min increments with seated rest breaks if needed 17

18 Physical Therapy Check-Ups for PD Every 6-12 months Pts can perform aerobic exercise as part of a comprehensive HEP Referral for H&Y 1-2 Future Directions Schenkman 2017 (n=128) High intensity treadmill training (80-85% HRR) in de novo patients Mean change in UPDRS motor score in the high intensity group was 0.3 (95% CI, 1.7 to 2.3) compared with 3.2 (95% CI, ) in the usual care group over 6 months Moderate exercise group was not different from usual care Nonfutility study larger sample to determine efficacy Community Tandem Cycling Program N=41 PD, tandem cycled 3x/week for 10 weeks with a healthy partner in a group setting Intensity of 60 min sessions: rpms, 60-75% of estimated max HR Medical screen was adequate, no stress test Improvements in gait (velocity, cadence), balance, and transfers 100% retention rate Pedaling for Parkinson s Community-based Model McGough 2016 Summary High intensity exercise is feasible in individuals with PD and stroke May be altering disease progression in PD and heightening recovery in stroke Motor and non motor improvements Changing CNS connectivity in PD Neuroplasticity vs. compensation Clinical implementations: aerobic exercise in conjunction with disease-specific intervention Is Exercise Medicine? Yes No 18

19 Acknowledgements Mandy Penko, PhD Liz Jansen, MA Susan Linder, PT, DPT, NCS Sara Davidson, PTA Cindy Clark, OTR/L Elise Baron, BS Andrew Bazyk, BS Nicole Zimmerman, MS Mandy Miller-Koop, PhD The PD studies were supported by a grant through the NIH R01NS R21 NS040154; Davis Phinney Foundation. Clinicaltrials.gov registration number NCT The stroke studies were supported by a grant from the NIH R03HD and American Heart Association 15MCPRP ClinicalTrials.gov registration numbers NCT , NCT References 1. Ridgel AL, Vitek JL, Alberts JL. Forced, not voluntary, exercise improves motor function in parkinson's disease patients. Neurorehabil Neural Repair. 2009;23: Hirsch MA, Farley BG. Exercise and neuroplasticity in persons living with parkinson's disease. Eur J Phys Rehabil Med. 2009;45: Keus SH, Bloem BR, Hendriks EJ, Bredero-Cohen AB, Munneke M. Evidence-based analysis of physical therapy in parkinson's disease with recommendations for practice and research. 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