High Intensity Aerobic Exercise Enhances Function in Parkinson s disease

Transcription

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 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 participants 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 a rehabilitation program for individuals with PD. Discuss the application of forced-exercise in the management of other diseases and conditions including obesity and 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 other neurological and nonneurological populations 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 d Therapeutic 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 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 Rehabilitation Models of PD Compensation vs. Neuroplasticity using cerebello-thalmo-cortical circuit to bypass the defective basal ganglia Wu 2013 Wu 2005, 2013 What can animal models tell us about forced exercise and neuroplasticity in PD? Forced exercise and neuroprotection in rodent models of PD Jay, do you know what paper this is from??? 2

3 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 Jay, will need to link video here 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 Proposed Forced-Exercise Mechanisms of Action 3

4 Estimated V02 max (ml/kg/min) UPDRS Motor III Score Closing the gap between animal and human studies Rationale for Forced-Exercise in PD 15 On DBS Patient A On DBS Patient B Decreased activation in cortical areas 10 5 Start Target 1 Impaired sensory-motor integration Degraded quantity and quality of sensory info Off DBS 10 5 End Off DBS Exercise rate is important (animal studies) Augment, not replace, voluntary efforts (robotic studies) Increase quantity and quality of afferent info. 0 Off DBS (4 hrs) + forced-exercise X Position (cm) Off DBS (4 hrs) + no exercise 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 Study enrollment EOT 2003 Post EOT 2006 Aerobic exercise improves fitness, only FE improves clinical ratings High intensity exercise improves UE motor function Forced Voluntary Baseline EOT 0 Baseline Mid EOT EOT+2 EOT+4-35% -28% -5% 4

5 High Intensity Exercise Induces CNS Changes Measured with fmri N=23 individuals with PD 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 EOT 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 Study Overview Screening & Consent Baseline Biking Stress Test (N=100) Participant screening FE (N=40) Baseline Testing On-Medication Off-Medication 3x/wk for 8 wks VE (N=40) End of Treatment (EOT) Testing Off-Medication EOT + 4 weeks Off-Medication Noexercise Control (N=20) 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 Dementia Other medical or musculoskeletal contraindications to exercise EOT + 8 weeks Off-Medication 5

6 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 CYCLE Trial Consort Diagram 99% of stress tests were normal 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 (on medication) 34 ± 9 35 ± ± 9 UPDRS (off medication) 38 ± ± ± 12 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) CYCLE Trial Training Example Example of HR training data from one exercise session and time spent in target HR range Both FE and VE exercised 3x/wk for 8 weeks; 60-80% of HRR High intensity exercise delays disease progression Disease Progression 6

7 High intensity exercise delays disease progression Does MDS-UPDRS III change from baseline (off medication) to EOT? High intensity exercise delays disease progression Group trajectories significantly differ over time. + Do the slopes differ by exercise group? Is there a significant difference between groups on mean MD- UPDRS III at EOT? Mean (95% CI) MDS-UPDRS III by exercise group over time. + FE and VE groups decrease significantly more compared to Controls. Mean MDS-UPDRS III scores are significantly higher at EOT 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 disease progression Does MD-UPDRS III change from baseline (on medication) to EOT? Does MDS-UPDRS III change from baseline (on medication) to baseline (off medication)? Medication and high intensity exercise have similar effects on disease progression 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 EOT? Mean (95% CI) MDS-UPDRS III by exercise group over time. + No evidence that baseline scores on medication differed from EOT scores. Mean (95% CI) MDS-UPDRS III by exercise group over time. Overall Results Gross Motor Outcomes 7

8 Total Trial Times (sec) NJS V (m) Mobility-Timed Up & Go Test: itug Individuals with PD display deficits in gait and turning performance which increases fall risk. 70% of PD subjects will develop gait and postural impairments 35-90% of these patients will experience at least one fall/year Despite such high fall rates clinicians do not currently have an effective and reliable method for characterizing fall risk itug provides a quantitative assessment of balance and gait during common daily tasks to accurately determine level of function. Mobility-Timed Up & Go Test: itug itug Data from IMU Sensor in ipad Outcome Measures from itug Time to complete task: Total Trial Time (sec) Gait: Normalized Jerk Score (NJS) of linear acceleration in AP, ML, V (m): higher values indicate increased dynamic movement and increased mobility Turning: Root mean square (RMS) of linear acceleration in AP, ML, and V (m): higher values indicate increased acceleration amplitude High intensity exercise improves overall mobility 8.8 3% High intensity exercise improves gait dynamics % Baseline On Baseline Off EOT EOT+8 Evaluation 4.0 Baseline On Baseline Off EOT EOT+8 Evaluation Significant difference from Baseline On Significant difference from Baseline On 8

9 High intensity exercise improves turning acceleration 6% High intensity exercise elicits increase in arm swing Baseline EOT Subject BG_014 VE group Left side affected Single-Task condition 56.6% Increase 10.1% Increase Significant difference from Baseline On Exercise Improves Walking Gait Baseline EOT Subject BG_026 VE group Right side affected Cognitive Outcomes Single-Task condition High intensity exercise improves information processing & motor performance High intensity exercise improves complex information processing 8% 7% Significant difference from Baseline On 9

10 Test Time (sec) High intensity exercise improves complex information processing & motor performance 8% 6% High intensity exercise improves motor performance 9% Significant difference from Baseline On Significant difference from Baseline On Computerized Trail Making Test (TMT) High intensity exercise improves visual scanning and motor performance on TMT Base_ON Base_OFF EOT EOT+8 Evaluation Significant difference from Baseline On High intensity exercise improves motor performance on TMT 8% High intensity exercise improves motor performance on TMT Significant difference from Baseline On Significant difference from Baseline On 10

11 Dwell Time (sec) High intensity exercise improves visual scanning/cognitive performance on TMT Cardiovascular Outcomes Base_ON Base_OFF EOT EOT+8 Evaluation Significant difference from Baseline On Aerobic exercise increases CV fitness Average Cadence During Exercise and Stress Test Exercise characteristics Forced exercise Voluntary exercise Control (no exercise) Average cadence during exercise 79 ± ± 15 Pre stress test average cadence Post stress test average cadence 64 ± 14 62± ± 13 70± 16 66± 13 62± 15 Maximal and submaximal VO2 increase for FE and VE Submaximal VO2 decreased over time in the control group Relationship Between Cadence and Peak VO2 Quality of Life At 60 rpms and greater, there is a linear relationship between peak VO2 and rpms As rpms increase, peak VO2 increases 11

12 High intensity exercise may improve depression symptomology Variable: Exercise (n=72): Control (n=19): Percent change pre to post: -8% (improvement) 15% (worsening) Number of participants depressed at baseline: Participants who improved depression categories: Participants who worsened depression categories: Participants with improved SRD: 12 1 Participants with worsened SRD: 9 3 Can FE be used to enhance Recovery of Function after Stroke? SRD: Smallest Real Difference detectable in daily living Applying high intensity exercise to individuals with stroke Hypothesis: Aerobic exercise will influence motor recovery and nonmotor function in individuals with stroke Prime the CNS via AE Intensive Motor Practice Anticipated Outcome: Those in the FE group will have a greater recovery of motor and non-motor function than VE and RTP alone Proposed Mechanism of FE after Stroke Study Aims To determine the differential effects of forced and voluntary exercise on motor function, non-motor function, and cardiovascular fitness in individuals with chronic stroke 12

13 Study Overview FE + RTP Screening & Consent Baseline Biking Stress Test Baseline Testing 3x/wk for 8 wks VE + RTP End of Treatment (EOT) Testing EOT Biking Stress Test EOT + 4 weeks RTP Only Repetitive Task Practice (RTP) Focus on maximizing reps Typically between reps of 1 task Type of practice Blocked, whole part Patient goal setting with reps or time Standing vs. Sitting Minimize rest time Incorporate ROM into functional activity Grading of activities Three Time-Matched Intervention Groups Training Example Intervention Intensity Intervention Intensity FE + RTP % HRR? % HRR VE + RTP 60-80% HRR? % HRR RTP only? % HRR? % HRR 45 min 45 min RTP videos Motor Outcomes 13

14 High intensity exercise improves gross motor function Non-Motor Outcomes Depression scores declined over time across groups Quality of life items improved over time across groups Quality of life cognitive composite score improves over time only among FE Cardiovascular Outcomes 14

15 Peak VO2 High intensity exercise improves cardiovascular fitness Mean Peak VO2 Baseline EOT Timepoint RTP VE FE Clinical Implementation What other equipment can be used for FE? Eliminating barriers to cycling intervention Keeping feet on pedals PD: Ridigity, 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 Clinical Translation Summary High intensity exercise is feasible in individuals with PD and stroke May be altering disease progression in PD Motor and non motor improvements Neuroplasticity vs. compensation Clinical implementations: aerobic exercise as HEP vs. in conjunction with disease-specific intervention 15

16 Is Exercise Medicine? First, I bike then, I fish. Yes No Acknowledgements Mandy Penko, PhD Liz Jansen, MA Susan Linder, PT, DPT, NCS Sara Davidson, PTA Cindy Clark, OTR/L Andrew Bazyk, BS Nicole Zimmerman, MS Tanujit Dey, PhD 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. Mov Disord. 2007;22: ; quiz Morris ME, Martin CL, Schenkman ML. Striding out with parkinson disease: Evidence-based physical therapy for gait disorders. Phys Ther. 2010;90: Leddy AL, Crowner BE, Earhart GM. Utility of the mini-bestest, bestest, and bestest sections for balance assessments in individuals with parkinson disease. J Neurol Phys Ther. 2011;35: Ellis T, Cavanaugh JT, Earhart GM, Ford MP, Foreman KB, Dibble LE. Which measures of physical function and motor impairment best predict quality of life in parkinson's disease? Parkinsonism Relat Disord. 2011;17: Ellis T, de Goede CJ, Feldman RG, Wolters EC, Kwakkel G, Wagenaar RC. Efficacy of a physical therapy program in patients with parkinson's disease: A randomized controlled trial. Arch Phys Med Rehabil. 2005;86: Wu T, Hallett M. The cerebellum in Parkinson s disease. Brain. 2013: 136; Colcombe S, Kramer AF. Fitness effects on the cognitive function of older adults: A metaanalytic study. Psychol Sci. 2003;14: References 10. Frazzitta G, Maestri R, Uccellini D, Bertotti G, Abelli P. Rehabilitation treatment of gait in patients with parkinson's disease with freezing: A comparison between two physical therapy protocols using visual and auditory cues with or without treadmill training. Mov Disord. 2009;24: Frenkel-Toledo S, Giladi N, Peretz C, Herman T, Gruendlinger L, Hausdorff JM. Treadmill walking as an external pacemaker to improve gait rhythm and stability in parkinson's disease. Mov Disord. 2005;20: Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, Poewe W, Sampaio C, Stern MB, Dodel R, Dubois B, Holloway R, Jankovic J, Kulisevsky J, Lang AE, Lees A, Leurgans S, LeWitt PA, Nyenhuis D, Olanow CW, Rascol O, Schrag A, Teresi JA, van Hilten JJ, LaPelle N. Movement disorder society-sponsored revision of the unified parkinson's disease rating scale (mds-updrs): Scale presentation and clinimetric testing results. Mov Disord. 2008;23: Goodwin VA, Richards SH, Taylor RS, Taylor AH, Campbell JL. The effectiveness of exercise interventions for people with parkinson's disease: A systematic review and metaanalysis. Mov Disord. 2008;23: Herman T, Giladi N, Gruendlinger L, Hausdorff JM. Six weeks of intensive treadmill training improves gait and quality of life in patients with parkinson's disease: A pilot study. Arch Phys Med Rehabil. 2007;88: Gobbi LT, Oliveira-Ferreira MD, Caetano MJ, Lirani-Silva E, Barbieri FA, Stella F, Gobbi S. Exercise programs improve mobility and balance in people with parkinson's disease. Parkinsonism Relat Disord. 2009;15 Suppl 3:S49-52 References 16. Keus SH, Munneke M, Nijkrake MJ, Kwakkel G, Bloem BR. Physical therapy in parkinson's disease: Evolution and future challenges. Mov Disord. 2009;24: Keus SH, Nijkrake MJ, Borm GF, Kwakkel G, Roos RA, Berendse HW, Adang EM, Overeem S, Bloem BR, Munneke M. The parkinsonnet trial: Design and baseline characteristics. Mov Disord. 2010;25: Miyai I, Fujimoto Y, Ueda Y, Yamamoto H, Nozaki S, Saito T, Kang J. Treadmill training with body weight support: Its effect on parkinson's disease. Arch Phys Med Rehabil. 2000;81: Miyai I, Fujimoto Y, Yamamoto H, Ueda Y, Saito T, Nozaki S, Kang J. Long-term effect of body weight supported treadmill training in parkinson's disease: A randomized controlled trial. Arch Phys Med Rehabil. 2002;83: Morris ME, Menz HB, McGinley JL, Huxham FE, Murphy AT, Iansek R, Danoudis M, Soh SE, Kelly D, Watts JJ. Falls and mobility in parkinson's disease: Protocol for a randomised controlled clinical trial. BMC Neurol. 2011;11: Pelosin E, Faelli E, Lofrano F, Avanzino L, Marinelli L, Bove M, Ruggeri P, Abbruzzese G. Effects of treadmill training on walking economy in parkinson's disease: A pilot study. Neurol Sci. 2009;30: Reid WG, Hely MA, Morris JG, Loy C, Halliday GM. Dementia in parkinson's disease: A 20- year neuropsychological study (sydney multicentre study). J Neurol Neurosurg Psychiatry. 2011;82: Morris ME. Movement disorders in people with parkinson disease: A model for physical therapy. Phys Ther. 2000;80:

17 References 24. Soh SE, McGinley J, Morris ME. Measuring quality of life in parkinson's disease: Selection of-an-appropriate health-related quality of life instrument. Physiotherapy. 2011;97: Tan D, Danoudis M, McGinley J, Morris ME. Relationships between motor aspects of gait impairments and activity limitations in people with parkinson's disease: A systematic review. Parkinsonism Relat Disord Termoz N, Halliday SE, Winter DA, Frank JS, Patla AE, Prince F. The control of upright stance in young, elderly and persons with parkinson's disease. Gait Posture. 2008;27: Chen H ZS, Schwarzshild MA, Hernan MA, Ascherio A. Physical activity and the risk of parkinson disease. Neurology. 2005;64: Alberts JL, Linder SM, Penko AL, Lowe MJ, Phillips M. It is not about the bike, it is about the pedaling: Forced exercise and parkinson's disease. Exerc Sport Sci Rev. 2011;39: Knaepen K, Goekint M, Heyman EM, Meeusen R. Neuroplasticity - exercise-induced response of peripheral brain-derived neurotrophic factor: A systematic review of experimental studies in human subjects. Sports Med. 2010;40: Gobbi LT, Oliveira-Ferreira MD, Caetano MJ, Lirani-Silva E, Barbieri FA, Stella F, Gobbi S. Exercise programs improve mobility and balance in people with parkinson's disease. Parkinsonism Relat Disord. 2009;15 Suppl 3:S Suchowersky O, Gronseth G, Perlmutter J, Reich S, Zesiewicz T, Weiner WJ. Practice parameter: Neuroprotective strategies and alternative therapies for parkinson disease (an evidence-based review): Report of the quality standards subcommittee of the american academy of neurology. Neurology. 2006;66: References 32. Dibble LE, Addison O, Papa E. The effects of exercise on balance in persons with parkinson's disease: A systematic review across the disability spectrum. J Neurol Phys Ther. 2009;33: Bergen JL, Toole T, Elliott RG, 3rd, Wallace B, Robinson K, Maitland CG. Aerobic exercise intervention improves aerobic capacity and movement initiation in parkinson's disease patients. NeuroRehabilitation. 2002;17: Mak MK, Yang F, Pai YC. Limb collapse, rather than instability, causes failure in sit-tostand performance among patients with parkinson disease. Phys Ther. 2011;91: Suchowersky O, Gronseth G, Perlmutter J, Reich S, Zesiewicz T, Weiner WJ. Practice parameter: Neuroprotective strategies and alternative therapies for parkinson disease (an evidence-based review): Report of the quality standards subcommittee of the american academy of neurology. Neurology. 2006;66: Wu T, Hallett M. A functional MRI study of automatic movements in patients with Parkinson s disease. 2005; 128,