1. Role for Exercise in Risk Factor Modification after Stroke: New Models of Task-Oriented Training Richard Macko, M.D. Baltimore Veterans Affairs Medical Center Director, Exercise & Robotics Rehabilitation Center of Excellence Geriatric Education Series November 30, 2006 No disclosures

2. Cardiovascular Disease Risk Factor Profiles after a Stroke  Recurrent stroke in 10-14% / 1 st year, 28-33% / 5 years  Coronary artery disease in 30–70%  Cardiovascular co-morbidities in 75%  Insulin resistance in 80% Current Health Care Model  Medical management is the cornerstone of contemporary tertiary stroke prevention. Medical Rx not enough….. Atherothrombotic risks remain high !

3. What is the role of exercise in current stroke rehabilitation care models? Current Care - Emphasizes early rehabilitation to improve ADL function; finished <3-6 months u Persistent neurological deficits in 75% u Inactivity & age-related declines propagate disability, and worsen CVD risk by promoting insulin resistance. No evidence-based recommendations to promote regular exercise in chronic stroke.

4. Percent of stroke patients with plateau in motor recovery while receiving conventional rehabilitation. Jorgenson et al. Arch Phys Med Rehabil 1995 N=804 95% get no better after 11 weeks with routine care.

5. What may be deficient in conventional rehabilitation models ? 1. Is exercise intensity enough to improve fitness and modify stroke and cardiovascular risk profiles ? u Typical 51 minute physical therapy session < 3 minutes of low aerobic intensity exercise. McKay Lyons et al. 2002 2. Is motor learning optimized ? u 20-30 minutes practice to produce short-term cortical motor adaptations in normal adults. Classen 1998 3.Do we exploit full time window for neuroplasticity ? u Motor control can be modified by training many years post-stroke, and this is associated with brain plasticity. Liepert 2001 Luft 2004

6. Multi-System Model of Neurological Disability Task-Oriented Exercise Interventions Target Cardiovascular Fitness HEALTH &FUNCTION OUTCOMES Neuroplasticity & Motor Learning Skeletal Muscle

7. - Outline - I. What is biologic rationale for Exercise after stroke: u Peripheral Mechanisms - Cardiovascular deconditioning & muscle abnormalities worsen disability & risk factor profiles by promoting insulin resistance. u Central Neural Mechanisms – task repetition to promote plasticity. II. What is the evidence that exercise can improve fitness & mobility function in chronic stroke: u Mechanisms of modifying metabolism - insulin sensitivity u Mediating brain plasticity in subcortical networks

8. How unfit are stroke patients? We tested fitness levels & energy demands of gait in 156 patients  Mean Age 67 + 8 years  Mean 3 years post-stroke  Hemiparetic gait, not wheelchair bound.

9. Lab Measures of Fitness & Efficiency of Gait Peak Effort TM Exercise Test u Test cardiopulmonary response to peak exertion. u V0 2 peak: Best measure of fitness. Economy of Gait u Purpose - estimate energy demands of hemiparetic gait u 75% of floor-walking pace u Rate of V0 2 calculated at steady state oxygen kinetics Macko et al. 1997 Dobrovolny et al 2003

10. Stroke patients have diminished fitness reserve Low Peak Fitness Levels u V0 2 Peak = 13.8 + 4 ml/kg/min; u 50 % below sedentary controls. Poor Economy of Gait : u Mean rate V0 2 9.7 + 2 ml/kg/min Controls Stroke 75% 27% * V0 2 ADLADL

11. Relationship of Peak VO 2 to Thigh Lean Tissue Mass (DXA) r=0.64, P<0.001

12. CT Scan of the Mid-Thigh Cross-Sectional Muscle Area in a Stroke Patient Muscle area is 20% lower in hemiparetic thigh (N=30, P<.001). Ryan et al. APMR 2002

13. Changes in Paretic Leg Skeletal Muscle Phenotype after Stroke Myosin Heavy Chain Profile Increased fast MHC isoforms in paretic leg quadriceps. Paretic leg = *67% Unaffected leg = 51% (*p<.001, N=15) Fast MHC  Insulin Resistance, Metabolic Syndrome Fast IIA IIX I (Slow) _______Rat_____ Tib Ant Soleus Patient #1__ Paretic NP __Patient #2___ NP Paretic DeDeyne et al. Muscle & Nerve 2004

14. Components of Metabolic Syndrome Metabolic Syndrome 3. Hypertension & Micro-Albuminuria 1. Insulin Resistance Glucose intolerance Hyper-insulinemia Type 2 diabetes 2. Dyslipidemia  Triglycerides  HDL-C 4. Central Obesity WC-M  102cm WC-F  88 cm “Lipo-toxicity” Report – NHLBI / AHA Circ 2004 Metabolic syndrome is more prevalent than T2DM and is an independent risk factor for stroke Najarian et al Framingham Offspring Study Arch Int Med 2006

15. What is Metabolic Syndrome? In non-stroke populations….. “Central Obesity” is the classical phenotype. Where’s the fat?

16. Relative fat content 25% higher in hemiparetic thigh (N=30, P<.001). Ryan et al. 2002  Intra-muscular area fat - Linked to Insulin Resistance pareticnon-paretic Low Density CT Scan Mid-Thigh Intra-Muscular Area Fat What unique body composition abnormalities propagate insulin resistance after stroke ?

17. Molecular mechanisms underlying insulin resistance & muscle atrophy after stroke TNF  = atrophy & insulin resistance Exercise lowers muscle TNF  to increase muscle mass & exercise improves insulin sensitivity (CHF, elderly). Ivey, Hafer-Macko et al 2005 Hafer-Macko Stroke 2005

18. Factors Related to Pathogenesis of Metabolic Syndrome Obesity & Lipotoxicity Advancing age Insulin Resistance & Inflammation Physical Inactivity NHLBI / AHA Circ 2004

19. - Clinical Significance - Insulin Resistance after HP Stroke 35% Diabetic by Med Hx. 46% IGT or T2DM by Fasting or OGTT 19% Normal IGT & T2DM predict a 2-3 fold increased risk for recurrent stroke Dutch TIA Trial – Stroke 2006 81% of HP stroke patients (N=216) have Impaired Glucose Tolerance (IGT) or T2 Diabetes Mellitus (T2DM) Ivey, Macko et al. Cerebrovasc Dis 2006

20. A change in our understanding of Risk Factors 2006 Can lifestyle modification including exercise improve cardiovascular-metabolic health ?

21. Can lifestyle modification reduce development of T2DM in high risk non-stroke populations?  Lifestyle Modification vs. metformin to prevent T2DM in adults at high risk: #1 Exercise & Wt loss #2 Metformin #3 placebo AGE REDUCTION IN INCIDENCE OF T2DM Lifestyle vs. PlaceboMetformin vs. Placebo 45-5959% *31% >60 71% *11% Diabetes Prevention Program shows lifestyle modification more effective than metformin to reduce progression to T2DM in high-risk non-stroke populations. *p<0.01 vs. placebo & metformin The Diabetes Prevention Program NEJM 2002

22. Biological rationale for regular exercise after stroke: u Physical deconditioning threatens capacity of stroke patients to meet high energy demands of hemiparetic walking. u Inflammatory-metabolic abnormalities in muscle propagate disability and increase cardiovascular and stroke risk by promoting insulin resistance. u Insulin resistance is an epidemic after stroke, and may be modifiable by exercise training.

23. Treadmill aerobic exercise as a model to promote locomotor re-learning Harris-Love et al. 2001 Harris-Love et al 2004 50% improved inter-limb stance:swing ratio. 30% improved symmetry of insole forces. 40% less cycle-cycle variability. Improved timing quadriceps activation.

24. Randomized Clinical Trial: TM Training in Chronic HP Stroke Purpose: Determine whether 6 months TM aerobic training (T-AEX at 60% HRR) improves CV fitness, insulin-glucose response during OGTT & walking function by neuroplastic mechanisms in chronic stroke patients, compared to controls. Reference Controls: u 45 minutes supervised stretching exercises u 5 minutes low aerobic intensity walking. u Time-matched exposure to health professionals

25. Subjects: Clinical & Demographic Features TM (25) Control (20) u Males : Females18 : 714 : 6 u Age (yrs) 65 + 10 63 + 8 u Hemisphere (R : L)10 : 13 9 : 11 u Time since stroke (M)32 + 30 42 + 65 u Assistive Device –None9 ( 37.5% ) 5 ( 24% ) –Single point cane9 ( 37.5% )12 ( 57% ) –Quad cane/walker 6 ( 25% ) 4 ( 19% ) u Floor Walking Speed 1.4 + 0.7 1.5 + 0.7 (range MPH)( 0.25 - 2.7 ) ( 0.19 - 2.6)

26. Does T-AEX improve cardiovascular fitness and efficiency (economy) of hemiparetic gait ?

27. RESULTS: Effects of TM-AEX on Fitness and Economy of Gait after Stroke  % V02 * * * P<0.02 NS

28. Relationship between progression in training velocity & fitness gains Only those that trained faster increased metabolic fitness. Progressing training velocity predicts increased V02 peak (r=0.43, P=0.017)

29. Does T-AEX training improve ambulatory function in chronic hemiparesis ? What is the evidence for exercise-mediated brain plasticity?

30. Effects of T-AEX (N=25) vs. control exercises (N=20) on 6-minute walk Macko et al Stroke - In Press * † * * P<0.005

31. Effect of T-AEX on Walking Impairment Questionnaire-Distance WIQ Distance Score * *† P<0.005

32. Evidence exercise-mediated brain plasticity fMRI Paretic Knee Movement Fulcrum and harness minimizes ballisitic head movement. BOLD fMRI shows similar patterns of brain activation with knee movement, as occur in walking. Luft et al. 2004 Johns Hopkins University

33. fMRI Paretic knee movement: Increased brain activation (post – pre) with TM training Activity dependent brain plasticity in chronic stroke TM N=14 Control N=14, Group x time, p < 0,05 Luft Neurosci Abstracts 2005 Red NucleusCerebellumIpsi-lesional Cortex

34. Cortico-Rubro-Cerebellar Pathways Dentate Olivary nuclei Spinal cord Cortex Red nucleus u RN fires during gait u Lesion= Hemiparesis in rodents u RN discharges during gait adaptation in higher mammals

35. Does T-AEX modify cardiovascular - metabolic risk factor profiles ?

36. Effect of T-AEX on Walking Impairment Questionnaire-Distance WIQ Distance Score * *† P<0.005

37. Evidence exercise-mediated brain plasticity fMRI Paretic Knee Movement Fulcrum and harness minimizes ballisitic head movement. BOLD fMRI shows similar patterns of brain activation with knee movement, as occur in walking. Luft et al. 2004 Johns Hopkins University

38. fMRI Paretic knee movement: Increased brain activation (post – pre) with TM training Activity dependent brain plasticity in chronic stroke TM N=14 Control N=14, Group x time, p < 0,05 Luft Neurosci Abstracts 2005 Red NucleusCerebellumIpsi-lesional Cortex

39. Cortico-Rubro-Cerebellar Pathways Dentate Olivary nuclei Spinal cord Cortex Red nucleus u RN fires during gait u Lesion= Hemiparesis in rodents u RN discharges during gait adaptation in higher mammals

40. Does T-AEX modify cardiovascular - metabolic risk factor profiles ?

41. * Baseline and Post-Intervention Mean Insulin Curves (T-AEX group) T-AEX reduces insulin area 25% *P<0.01 ANOVA TM (N=25) vs. Controls (N=20)

42. Effects of TM training on glucose response (OGTT) TM training does not alter glucose response across entire TM group. TM- reduces glucose area 14% *P<0.05 for patients with baseline impaired glucose tolerance TM (N=12) ALL IGT only *

43. Control Participant Treadmill Participant Pre- post- P NPC NP PTM Restoration of slow myosin heavy chain (MHC) More sensitive to action of insulin Potential Mechanism for Improved insulin sensitivity Leg muscle Myosin Heavy Chain electrophoresis

44. SUMMARY: TM Training in Chronic Stroke 1. Improves fitness 2. Improves insulin & glucose metabolism 3. Improves walking function 4. Locomotor gains linked to brain plasticity in cortical – subcortical networks.

45. Public Health Implications: I. Exercise can improve mobility function even years after stroke. II. Brain plasticity in subcortical rubro-cerebellar networks may underlie functional motor benefits. III. Cardiovascular fitness & metabolic health are modifiable risk factors improved by exercise. Larger studies needed to determine whether exercise can prevent recurrent stroke and progression to diabetes.

46. October 23-24, 2006 Adequacy of Evidence for Physical Activity Guidelines Development National Academy Science Adequacy of Evidence for Physical Activity Guidelines Development October 26, 2006 DHSS – plans to develop: Evidence-based guidelines for Physical Activity for all Americans, including aging and disability conditions. NEWS

47. Thanks to Collaborators Baltimore VA Gerontology/Neurology/Nursing & University Maryland :  Andrew P. Goldberg, MDKathleen Michael, PhD, RN  Alice Ryan, PhDCharlene Hafer-Macko, MD  Fred Ivey, PhD Marianne Shaghnessy, CRNP, PhD  John Sorkin, MD, PhDLeslie I Katzel, MD, PhD  Steven Kittner, MD M.PHSusan Kopunek, RN  Barbara Resnick, RN, PhDShawnna Patterson, MD, PhD University of Maryland Physical Therapy & Rehabilitation Science:  Larry Forrester, Ph.D.Jill Whitall, Ph.D.  Mary Rodgers, Ph.D.,P.T. Sandra McCombe-Waller, Ph.D., PT Tubingen, Germany: Andi Luft, M.D. Johns Hopkins: D. Hanley, M.D.