Exercise in Parkinson s the new drug

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1 Exercise in Parkinson s the new drug Bhanu Ramaswamy MCSP 19th/20th March 2010 ACPIN Residential Conference Fit for Life? Exercise and Neurology Northampton

2 Aims; no particular order & simple Augment the Spring Conference Key Note lectures (icsp soon!) To consider how cellular biology and animalmodel research are increasing evidence. Translate the information into a framework for exercise and Parkinson s Intersperse with discussion on the Parkinsonian relevancies of emerging evidence that might influence clinical practice Briefly consider what might sustain habits and interest in exercise for people with Parkinsonism

3 100% Causative factor Neurorestoration NICE CG 35 (2006) Dopaminergic neurones Treatment commenced Neurorescue Neuroprotection Time

Maintains neural function by neurotrophic support enhancing learning and memory So exercise may be powerful in augmenting synaptic

4 Exercise at molecular level Two-fold effect by up-regulating brain-derived neurotrophic factor. 1. Facilitates synaptic function by increasing plasticity in injured CNS and spinal cord to and promotes neuronal repair 2. Maintains neural function by neurotrophic support enhancing learning and memory So exercise may be powerful in augmenting synaptic plasticity, promoting behavioural rehabilitation, and counteracting the deleterious effects of aging. (Vaynman and Gomez-Pinilla (2005) Neurorehabilitation and Neural Repair 19 (4)

Animal models (Petzinger, Zigmond, Fisher) Mice, rats, rabbits, gerbils & primates Lesion the animal (induce Parkinson s), experiment, euthanise then investigate! 1.

5 Animal models (Petzinger, Zigmond, Fisher) Mice, rats, rabbits, gerbils & primates Lesion the animal (induce Parkinson s), experiment, euthanise then investigate! 1. Studies in rodent models (rats and mice love to run 9 hours / day!) provide positive effects on dopaminergic neurotransmission. 2. Forced exercise (forced to maintain running speed greater than preferred pace), usually treadmill, improves motor function and is neuroprotective in Parkinsonian-treated animals 3. Modulate genes and proteins important to basal ganglia function

6 What of pre-disease state? If regular (intense) exercise can protect the brain and improve the capacity for self-repair, the hypothesis is that damage can be reduced by prior motor training So exercise animals hard (forced exercise), review the neuro-protective effects of motor exercise using a chemical that would normally destroy dopamine neurons. In exercised animals, the vulnerability of dopamine neurons were reduced with less dramatic effect to nervous system (Smith and Zigmond 2003 Experimental Neurology 184 (1) 31-39)

7 Person perspective of benefits Sheffield PD Class cohort 2006 It makes me feel I can maximise my (physical) potential Allows me to remain fit (and possibly healthy) Limits dependence on my spouse Gives me freedom am back driving, shopping unsupervised, arm less painful

flexibility, balance ) Functional status outcomes (increased stride length,

8 Therapeutic expectation Minimise effects of disease progression (neuroprotection) Physiological effects (increased dopamine levels, endurance, flexibility, balance ) Functional status outcomes (increased stride length, distances, independence) Psychological (stress levels, well-being) Social (involvement and support)

Strength examples and variety Dibble 2009, 2006

general rehabilitation) Hirsch 2003, 1996 balance

Toole 2000 balance and strength (Reuter 1999 gym

9 Strength examples and variety Dibble 2009, 2006 ergometer resistance and intensity (Ellis 2005 general rehabilitation) Hirsch 2003, 1996 balance and resistance Scandalis 2001 lower limb weights Toole 2000 balance and strength (Reuter 1999 gym and pool) (Bridgewater trunk-specific aerobics) N.B. (Brackets indicate programmes for which strength was one part but not the main outcome of the sessions)

10 Yoga (Discursive) Tai Chi (Lee et al 2008 critical review, Hackney 2008, Li et al 2007 pilot,) Dance Tango (Hackney and Earhart ) Argentinean tango better than ballroom plus paired better than non-paired Exercise styles

11 Lifestyles and PD Conductive education Bandyopadhyay et al 2002, Yekutiel et al 1991 Pilates - none Alexander technique Stallibrass 2002, 1997

12 Relevancies 1: BG dysfunction Impaired performance of well learned motor skills and movement sequences Problems maintaining sufficient movement amplitudes (sensori-motor feedback) Difficulty performing two or more well learned tasks simultaneously Difficulty shifting motor and cognitive sets Increased time for mental processing

Relevancies 2: Classifications 1. Primary (idiopathic) parkinsonism ++ 2. Secondary (acquired, symptomatic) + 3. Heredodegenerative parkinsonism 4.

13 Relevancies 2: Classifications 1. Primary (idiopathic) parkinsonism Secondary (acquired, symptomatic) + 3. Heredodegenerative parkinsonism 4. Multiple system degeneration (parkinsonism plus syndromes). Features, such as tremor, early gait abnormality (e.g. freezing), postural instability, non-motor and response to levodopa, can be used to differentiate PD from other parkinsonian disorders. Jankovic 2008

14 Relevancies 3: Subtypes Variable course of progression and symptom implies different biochemical or degenerative mechanisms. Early disease onset (25%) longest duration till death, delay before falls and cognitive decline Tremor dominant (31%) same life expectancy, falls history and hallucinations as non-tremor dom Non-tremor dominant (36%) strong association with cognitive impairment (Lewy body pathology) Rapid disease progression without dementia (8%) older, early depression, midline symptoms, often tremulous onset, increased mentation, freezing and ADL (UPDRS Part I and II) subscores (Selikhova et al 2009 Brain;132(11); ; Schrag et al 2008 Mov Disord 22(7) ; Jancovic and Kapadia (2001) Arch Neurol; 58: )

Relevancies 4: Dual tasking Clinical debate re: multi-, dual- & uni-tasking Shown to slow responses RESCUE studies (Rochester

Difficulty in self-pacing, reaction time prolonged & abnormal pre-movement EEG, sensory scaling and sensorimotor integration.

treatments or cues decreases Surgery a possible solution e.g. bilateral subthalamic nucleus stimulation.

15 Relevancies 4: Dual tasking Clinical debate re: multi-, dual- & uni-tasking Shown to slow responses RESCUE studies (Rochester et al 2007 Journal of Neural Transmission 114 (10) ) Bradykinesia main culprit. Difficulty in self-pacing, reaction time prolonged & abnormal pre-movement EEG, sensory scaling and sensorimotor integration. If use compensation strategy (cue), engagement of processes further reduces other task performance Response to L-dopa treatments or cues decreases Surgery a possible solution e.g. bilateral subthalamic nucleus stimulation. Might remove interfering signals; more efficient compensation by other cortical mechanisms, especially postural control. Schrag et al 2008 Mov Disord 22(7) ; Maurer et al 2003 Brain 126 (5)

Relevancies 5: Freezing Macht et al 2007 Mov

Freezing is significantly associated with longer

more likely in men than in women and in patients

16 Relevancies 5: Freezing Macht et al 2007 Mov Disord 22(7) Freezing is significantly associated with longer disease duration and advanced stage of the disease.? Relation with dualtasking Freezing episodes more likely in men than in women and in patients taking, in addition to levodopa, Entacapone, Amantadine, or dopamine agonists. Less common in tremor-dominant Different response on / off

17 In summary From animal (and some human) models: Exercise is beneficial BUT for neuroprotection and possibly rescue the F.I.T. principles must be higher (60% MHR) than currently undertaken Only evidenced as modifiable in early disease or new onset (traumatic) if hope for rescue element Specifically targeted and reward driven Complexity to be considered to utilise wider brain function. Hirsch M, Farley BG Eur J Phys Rehabil Med 45(2) )

18 Possible symptomatic framework Brady / hypokinesia flexibility, then speed, amplitude and sensory Rigidity flexibility and rotatory action Tremor nil specific; as a consequence of upper limb weight bearing activities Postural instability - extensor activity and postural activation of agonoist/antag Freezing decrease speed, find overiding cue?

stage) (See Nieuwboer Spring Conference Key note

19 Condition stage Clinical model not considered in full Targeted exercise (earlier stage) Cued exercise (later stage) (See Nieuwboer Spring Conference Key note lecture) F.I.T.T principles Frequency Intensity Time (duration) Type

20 F.I.T.T principles (ACE & PD literature) IDEAL Frequency Intensity Time (duration) Type Endurance Start 2 3 x week for 3 months, then decrease to weekly 68 80%* MHR. Higher intensity if less frequent *Neuroprotect. Incremental increase to 150 mins / week (aim for mins sessions) Power walk, Treadmill, Nordic walk, run, cycle (group) Flexibility & posture Part of warm up each time exercise is undertaken Up to 5 major body areas selective if to work specifics 10 sec before and 30 sec stretch after session Separate stretch or part of increased amplitude exs Strength 2-3 x week 5 12 reps for 5 10 major m/s groups (10 rep max; large groups before small) Not as important as rest necessary according to state of muscles Free weights, body weights, machines, hydrotherapy, cycle

21 Finally, additional considerations Current fitness Consider a diary for accuracy and monitor progress Medication cycle and disease stage Use of enhancing cues / cueing strategies Appropriate environment Adherence (10 30% in trials) Sustain through longer term education = behavioural change Motivation = Choice, support and reward Transport and toilets = impede enjoyment Enjoyment = groups Fit lifestyle

PD ExpertBriefing: The Effects of Exercise on PD

PD ExpertBriefing: The Effects of Exercise on PD Led By: Margaret Schenkman, P.T., Ph.D., F.A.P.T.A. Associate Dean for Physical Therapy Education, and Director, Physical Therapy Program, University of