exercise interventions targeting neuroplasticity and

Exercise Interventions Targeting Neuroplasticity and Neuroprotection in Adults with Neurodegenerative Diseases January 24, 2013; EL McGough, N Kirk-Sanchez, JG Moore, M Nelson. Not to be copied without permission.

1

APTA Combined Sections Meeting 2013

San Diego, CA January 21-24, 2013

Exercise Interventions Targeting Neuroplasticity and Neuroprotection in Adults with Neurodegenerative Diseases

January 24, 2013 11:00 AM - 1:00 PM

Ellen McGough, PT, PhD Department of Rehabilitation Medicine, University of Washington, Seattle, WA Neva Kirk-Sanchez, PT, PhD Department of Physical Therapy, University of Miami, Coral Gables, FL James G. Moore, PhD, PT, PCS Department of Physical Therapy, University of Miami, Coral Gables, FL Mark Nelson, MPT, Clinical Coordinator Physical Therapy, UW Medicine Northwest Hospital, Seattle, WA COURSE DESCRIPTION: Exercise interventions targeting neuroprotective mechanisms in adults with neurodegenerative diseases will be presented including mode, frequency, intensity and duration. Potential mechanisms and evidence related to exercise interventions for Alzheimer's disease (AD), Parkinson's disease (PD) and Multiple Sclerosis (MS) will be discussed. Innovative approaches that address barriers and challenges to exercise implementation will be described.

OBJECTIVES: Upon completion of this course, participants will be able: 1. To discuss potential neuroplastic and neuroprotective mechanisms of exercise in neurodegenerative disease processes, including Alzheimer's disease, Parkinson's disease and Multiple Sclerosis. 2. To describe evidence-based exercise interventions including mode, frequency, intensity, and duration of exercise interventions for individuals with neurodegenerative disease. 3. To describe considerations for evaluating exercise capacity (e.g. aerobic capacity) in adults with neurodegenerative disease. 4. To describe characteristics of delivery systems that address cognitive, physical and environmental barriers to exercise in adults with neurodegenerative disease.


2

Part 1: Neuroprotective Mechanisms of Exercise in Neurodegenerative Disease

I. Alterations in structure and function occur in the aging brain

a. May be unrelated to neurodegenerative disease

b. Nervous system changes with neurodegenerative disease

i. Neurodegenerative dementias (AD and MCI)

ii. Multiple sclerosis

iii. Parkinson’s disease (Petzinger, 2010)

II. Executive function is most affected in the aging brain – and most prone to neurological insult

by neurodegenerative disease

a. Executive function

b. Processes that show greatest rates of decline remain highly plastic (Colcombe 2004;

Honea 2010)

III. Older adult brains have some capacity for plasticity – a natural capacity that can be modified

by aerobic exercise

a. Electrical, synaptic, and morphologic properties of neurons change constantly

throughout their lifespan (Erickson and Kramer 2008)

b. Functional re-organization of sensory and motor pathways following injury is a widely

documented phenomenon (Pantano, Mainero, Caramia, 2006)

IV. Neuroprotection and neurodegeneration occur via many mechanisms

a. Vascular and cardiovascular

i. HTN (Waldstein, 2003)

ii. DM (Roberts 2008) and insulin resistance (Craft 2005; 2006)

iii. Cardiovascular risk factors and exercise

b. Inflammatory factors (Yaffe 2003; 2004)

i. Inflammation and hyperinsulinemia (Craft 2006)

ii. Inflammation and MS (White and Castellano 2008)

iii. Inflammation and exercise

c. Neurotrophins

i. Neurotrophins and exercise in animal studies (Ahlskog 2011; Cotman and

Bechtold 2007)

ii. Neurotrophins and MS (White and Castellano 2008; Gold 2003)

iii. Neurotrophins and exercise (Seifert 2010)

d. Neurotransmitters


3

i. Neurotransmitters and PD (Hirsch and Farley 2009; Vuckovic 2010)

ii. Neurotransmitters and exercise

e. Synaptogenesis and neurogenesis

i. Brain volume (Bugg and Head 2009; Erickson 2009; Burns 2008)

ii. Cortical connectivity

1. Young vs. old brains (Colcombe 2004)

2. Cortical connectivity and MS (Prakash 2007; 2010)

f. Sensory-Motor input

i. Information processing: a common causal factor in motor and cognitive decline

ii. A potential pathway for interventions that target both physical and cognitive

performance.

Part 2. Evidence: Neuroprotective Effects of Exercise in Adults with Neurodegenerative

Disease

I. Theoretical Model: Exercise, Physical Performance & Cognitive Health

II. Relationships between Physical and Cognitive Function

(McGough 2011; Aggarwal 2006; Waite 2005; Marquis 2002)

III. Measures of Neuroprotective Effects

a. Brain structures

b. Cognitive function

c. Physical function

d. IADL/ADL function

IV. Effects of Exercise in Older Adults

(Coulcombe 2006; Erickson 2010; Smiley-Oyen 2008; Hill 1993; Voss 2010)

a. Neuroplastic effects

i. Increased brain volume & function

ii. Improved cognitive function

iii. Improved motor function

iv. Improved complex tasks & daily function

b. Neuroprotective effects

i. Reduced brain volume & function

ii. Less cognitive function decline

iii. Less motor function decline


4

iv. Less decline in complex tasks & daily function

V. More Physical Activity Associated with Lower Incident Neurodegenerative Disease

a. Less global cognitive decline (MMSE) (Yaffe 2001; van Gelder 2004)

b. Less incident mild cognitive impairment (Geda 2010; Middleton 2008)

c. Less incident dementia (Larson 2006; Rovio 2005)

d. Lower risk for Parkinson’s disease (Chen 2005; Thacker 2008; Xu 2010)

e. Preliminary evidence between PA & MS risk (Motl & Fernhall 2011)

VI. More Physical Activity Associated with Better Cognitive Function

(Clarkson-Smith & Hartley 1989; Hillman 2006; Bixby 2007; Angevaren 2007)

a. Global cognitive function

b. Spatial memory

c. Reasoning

d. Executive function & mental flexibility

i. Working memory

ii. Reaction time

iii. Processing speed

VII. Cardiorespiratory Fitness & Cognitive Function

a. Older adults without cognitive impairment: Higher VO2peak associated with higher accuracy

on a spatial memory task, after adjusting for age, sex and education. (Erickson 2009)

b. Older adults with early Alzheimer’s disease: Higher VO2peak associated with better delayed

memory, attention & executive function. (Burns, 2008)

VIII. Evidence of Neuroplasticity with Aerobic Exercise in Older Adults

a. Brain Structure & Function

i. Neuroplasticity in selected brain structures

ii. Moderate intensity aerobic exercise enhances brain volume in frontal and

anterior hippocampus regions of the brain in healthy older adults. (Colcombe

2006; Erickson 2010)

iii. Increased cortical connectivity (Voss 2010)

b. Cognitive Function: Preservation or enhancement of cognition, especially executive

function and spatial memory.

i. Resistance exercise enhances cognitive function (Casilhas 2007; Liu-Ambrose

2010)


5

ii. Aerobic exercise enhances spatial memory and executive function (Colcombe

2006; Erickson 2010)

IX. Associations between Cardiorespiratory Fitness and CNS Health in Neurodegenerative

Disease

a. Alzheimer's disease (Burns 2008)

b. Parkinson's disease (Ahlskog 2011)

c. Multiple Sclerosis (Prakash 2010)

X. Dementia: Effects of Exercise

(Roach 2011; Hauer 2011; Blankevoort 2010; Kwak 2008; Heyn 2004; Teri 2003)

a. Outcomes:

i. Cognitive function - small gains in global cognitive function

ii. Mood & behavioral symptoms - improved

iii. Physical performance improved in mild-moderate dementia

a. Gait speed

b. Balance

c. Endurance

iv. IADL/ADL - Improved ADL all stages of dementia

b. Interventions:

i. Exercise + behavioral management

ii. Multicomponent exercise programs - most effective in enhancing function

iii. Functional training + progressive resistive exercise

iv. Activity-specific exercises

XI. Parkinson's Disease: Effects of Exercise

a. Outcomes:

i. Cognitive function (Rigdel 2010)

ii. Physical performance (Cochrane Database Syst. Rev., 2012; Schenkman 2012;

Shulman 2012; Rigdel 2009, Fisher 2008)

i. Walking economy

ii. Gait speed

iii. Upper extremity motor function

iv. UPDRS - motor

iii. IADL/ADL

iv. Mood & quality of life


6

b. Exercise Interventions

i. Walking

ii. Augmented

1. Treadmill training - body weight-supported

2. Tandem bicycles

3. Electric-assist bicycles

iii. Balance training

iv. Multicomponent programs

c. Factors Associated with Exercise Behavior (Rimmer 2010, Ellis 2011)

i. Personal factors: Self-Efficacy, preference, ability

ii. Environmental factors

XII. Multiple Sclerosis: Effects of Exercise (Molt & Pilutti, 2011)

a. Cognitive function: limited evidence

b. Physical performance (Dalgas 2008)

c. Aerobic capacity i. Disability status (EDSS scores)

ii. Sample population in most studies included subjects with EDSS scores < 7.

iii. Relationship between degree of training adaptation and disability (EDSS) is

inconclusive:

1. Low group (EDSS < 3.5-4.5) showed a larger increase in exercise time and

VO2 max (Shapiro, 1988, Ponicthera-Mulcare, 1997)

2. High function group experienced largest improvement (Mostert, 2002)

3. Equal improvement in VO2 max (Petajan1996)

XIII. Addressing Barriers in Effort to Sustain Effective Exercise Dosage

a. Alzheimer’s disease

i. Structured & supervised exercise

ii. Activity-specific (Roach 2011)

iii. Multicomponent exercise

iv. Behavioral intervention (Teri, 2003, 2005)

b. PD & MS:

i. Structured & supported exercise (physical + cognitive impairment)

ii. Augmented exercise (Rigdel 2009, Alberts 2011)

iii. Self-efficacy (Ellis 2011)


7

iv. Environment & social support are important

XIV. Factors Impacting Neuroprotective Response to Exercise

a. Pathology type (e.g. vascular, AD pathology)

b. Exercise type

c. Dose-response relationship

i. Intensity, frequency & duration

ii. Total exercise time

d. Personal & Environmental Factors

i. Age matters, but neuroprotective at all ages

ii. Sex – females benefit more

iii. Education

iv. Self-efficacy

v. Social support

XV. Summary: Neuroprotective Effects of Exercise in Adults with Neurodegenerative Disease

i. We have evidence of neuroprotective effects of exercise from animal and human

studies.

ii. Exercise interventions designed to achieve an effective dosage may enhance both motor

and non-motor functions in people with neurodegenerative diseases.

iii. Exercise interventions designed to target neuroprotective effects must address physical,

cognitive, personal and environmental barriers.

iv. Further research is needed to identify optimal exercise parameters.

Part 3. Considerations for Exercise Capacity Testing in Adults with Neurodegenerative

Disease

I. Special Considerations for Exercise Testing (Protas EJ, 1997)

a. Is maximal testing necessary for accurate exercise prescription for people with neuro-

degenerative disease?

b. Can it be achieved?

c. Is it accurate and reliable?

d. Can it be done safely?

e. Uniform exercise testing guidelines assume no health condition that would influence HR

and BP response (see ACSM: 70-85% of age predicted heart rate)

f. Multiple studies demonstrate abnormal cardiac responses to exercise in people with PD


8

II. Exercise Testing Decision Making

a. Choose appropriate mode relative to degree of impairment, safety

i. Treadmill (free movement vs. body weight supported)

ii. Various cycle ergometers (standard/recumbent)

iii. Upper extremity ergometers

b. Special Considerations for Exercise Testing in People with AD (Rimmer 1997)

i. Formal lab testing may be impossible (cognitive status, agitation)

ii. Consider AM testing if possible

iii. Refer to ACSM testing guidelines for elderly populations

iv. Limited support in literature for advanced disease

v. Disease effect on exercise response

vi. Limited literature especially in advanced disease

vii. Deconditioning associated with depression

viii. Consider side effects of medication

ix. Orthostasis

x. Balance impairment

xi. Cardiac arrhythmia

c. Maximal Exercise Testing in People with Early Stage AD: Modified Bruce protocol

(Billinger 2011)

i. VO2 peak was lower than that of non-demented peers

ii. ACSM normative values of fitness

iii. 10th-15th percentile for women with AD

iv. 15-20th percentile for men with AD

d. Alternative Methods for Estimating Exercise Capacity in People with Advanced

Dementia

e. Special Considerations for Exercise Testing in People with PD (Protas 1997)

i. Physical mobility constraints

ii. Physiologic limitations

iii. Chronotropic incompetence

iv. Lower absolute maximal heart rate

v. Orthostatic hypotension

vi. Compromised cardiovascular reflexes


9

vii. Patients with PD represent age groups having higher likelihood of cardiovascular

disease

viii. Anti-parkinsonian medication contribution to cardiac arrhythmia

(Stanley 1999)

ix. Pharmacotherapy Considerations:

1. Consider testing on and off medication to establish ranges of performance

2. Test at peak dose when possible

3. Peak effect may increase incidence of tachycardia and dyskinesias

4. Ask about recent changes in medication – results may be unpredictable

5. Medication levels can influence exercise performance

f. Disease Effect on Exercise Response in PD

i. PD exercisers may demonstrate great variability in heart rate response to the

same activity

ii. HR performance should be closely followed

iii. Exercise performance stability may depend on consistent exercise time relative

to last medication dose

iv. Exercise may alter drug absorption or metabolism rates causing changes in

symptomology

v. Baseline symptoms behavior should be documented across medication levels

g. Maximal Exercise Testing in People with Early Stage PD: Cardiorespiratory fitness

(VO2peak) testing - Treadmill testing highly reliable in mild to moderate PD (Hoehn & Yahr

1.5-3.0) (Katzel 2011)

h. Special Considerations for Exercise Testing in MS

i. Spasticity

ii. Incoordination

iii. Balance impairment

iv. Fatigue

v. Muscle weakness

vi. Sensory loss

vii. Cardiovascular dysautonomia

viii. Heat sensitivity

i. Marked Reductions in Exercise Capacity with Mild Degree of Disability in Patients with

MS (Kuspinar 2010)


10

i. Chose submaximal testing

ii. Indicated good predictor of exercise capacity

iii. Motl et al (2012) developed regression formula predicting VO2 peak

iv. Within 10% of true value in 95 of 100 patients with MS (mild disability)

j. Disease Effect on Exercise Response in MS

i. Attenuated HR and BP response during exercise in patients with MS

1. Cardiovascular dysautonomia

2. Many Patients with MS will experience fatigue before attaining age predicted

maximal heart rate

3. Inadequate rise in systolic BP during exercise may lead to insufficient perfusion

of brain or muscles

4. Premature exertion – lightheadedness, muscle fatigue

ii. Estimate of functional aerobic capacity - use actual HR response from graded

exercise test to prescribe target HR range for training

iii. DMA and pharmacological management of symptoms (i.e., Baclofen, tizanidine,

amantadine, fluoxetine, prednisone) may have side effects that alter exercise

response, exercise tolerance or both.

k. Mode for Clinical Exercise Testing on MS

i. Upright or recumbent leg cycle ergometer

• Safety due to LE sensory loss, weakness (foot drop), spasticity, and/or clonus

• Toe clips, heel straps

ii. Combination arm-leg ergometer

• Increase activated muscles and improve test results – greater cardiopulmonary

stress achieved

iii. Arm crank ergometer

• More severely impaired individuals, UE fatigue before cardiopulmonary maximal

response achieved

iv. Treadmill

• Low EDSS scores, safety not an issue

l. Exercise Testing and Training Conditions for Patients with MS

i. Morning optimal time

ii. Use a fan for cooling

iii. Monitor HR and BP


11

iv. Testing

v. Continuous or discontinuous protocol of 3 to 5 minute stages

vi. Begin with warm-up of unloaded pedaling/cranking

vii. Increase work rate for each stage by approximately 12 to 25 W (legs) and 8 to 10

W (arms)

viii. Use category – ratio RPE scale to estimate stress level

ix. Test termination:

§ Volitional fatigue

§ Reached MHR

§ Decrease or plateau in O2 consumption (VO2) with increasing

work rate.

m. Considerations for Exercise Test Interpretation in MS

i. Psychological dimension

ii. Cognitive deficit

iii. Memory loss

iv. Increased processing time

v. Disease progression

vi. Variation in symptoms daily

vii. Medication

viii. Sleep

ix. Temperature

x. Exacerbation

xi. Stop exercise until full remission

xii. Reassess

xiii. Temperature

xiv. Attenuated or absent sweating

xv. Utoff’s phenomena

xvi. Hydration

xvii. Urinary incontinence may cause individual to reduce fluid intake

III. Exercise Recommendations: Targeting Neuroprotective Mechanisms

a. Foundational assumptions

i. Exercise prescription must be tailored to the individual


12

ii. Best prescriptive “power” requires exercise testing

iii. Individuals with NDD exhibit altered exercise responses that have to be accounted

for in Rx

iv. Goal – attain brain-beneficial effects of exercise while maintaining safety

b. Foundational assumptions (Cotman 2007)

i. Overall brain health

ii. Brain resilience

iii. Improved learning and memory

iv. Growth factor cascade stimulating

v. Plasticity

vi. Neurogenesis and cerebrovascular perfusion

c. Foundational assumptions

i. Protective effects of exercise

ii. Reduces risk factors for cognitive decline

iii. Slows the rate decline in established disease

iv. Reduces inflammation which interferes with growth factor signaling

v. Improved oxygen transport systemically

vi. Pulmonary efficiency

vii. Cardiovascular efficiency

viii. Increased glucose sensitivity

d. What level of metabolic challenge best produces neuroprotective effects?

i. What percentage of VO2 peak is that for

ii. Healthy adults, older adults

iii. Adults with neurodegenerative disease (NDD)

iv. Older adults with NDDs

v. Advanced stages of NDDs

e. Targeting Cardiovascular Fitness (Colombe & Kramer 2003)

i. Combined aerobic & strengthening greatest effect

ii. Longer duration (> 30 min) had greater effect

iii. Greatest effect on executive function

iv. PA is beneficial to all cognitive functions

v. Ages 60-70 benefitted the most

vi. Studies with > 50% female reported greater benefit than studies with >50% male


13

f. Targeting Glycemic Control (Karstoft 2012; Umpierre 2011)

i. Interval training more effective in improving VO2max and glycemic control in people with

type 2 diabetes than steady paced walking

ii. Interval training: 3 min low intensity/3 min high intensity

iii. Steady Pace: continuous moderate walking x 60 min.

iv. Structured exercise training that consisted of aerobic, resistance, or both for ≥ 150

min/wk associated with improved glycemic control in type 2 diabetes.

v. Structured exercise training more effective than physical activity advice alone.

g. Implementation: Addressing Barriers Using the ICF Model

a. Health Condition

b. Personal Factors

c. Environment

d. Body Systems

e. Activity

f. Participation

h. Exercise Interventions Designed to Accommodate:

i. Body systems barriers

i. Slowed motor function

ii. Gait & balance impairments

ii. Cognitive barriers

i. Executive function deficits

ii. Memory impairment

iii. Social & environmental barriers

i. Implementation: Addressing Cognitive Impairment (Teri 2008)

1. Easy-to-remember increments

2. High repetition and lots of practice

3. Cognitively intact “study partner”

4. Written instructions (laminated, small magnets attached to the back of the page)

5. Visual memory cue

6. Handy reminder of how to do exercises

7. Make it fun and Individualized

j. Implementation: Addressing Cognitive Impairment (Mehrholz 2010; Kwakkel 2007; Keus

2007; Ellis 2011)


14

i. Health Condition: Pathology

ii. Body Systems:

a. Communication – exertion level, discomfort

b. Heart rate monitor

c. Cognitive-behavioral interventions

iii. Environment (room temperature, distractions)

a. Staff Training

b. Supervision- safety on equipment, cues/strategies to maintain intensity, task-

specific training

c. Structure and routine

d. Storage place for equipment

e. Fun

iv. Personal Factors

a. Self-efficacy

b. Preferences

c. Dyad model

d. Opportunity social interaction

e. Circuit Training, Virtual Reality Training

k. Prevention of Chronic Disease: ACSM/AHA Physical Activity Recommendations

i. ≥150 min/wk of physical Activity

ii. ≥ 30 min of moderate PA at least 5 days/wk,

iii. OR ≥ 20 minutes of vigorous PA at least 3 days/wk.

iv. Supervised by professional

v. Individually designed and tailored

vi. Behaviorally-base interventions & change strategies

vii. Education on progression

viii. Enjoyable

l. Prevention of Chronic Disease: Aerobic Exercise Dose - Intensity/Frequency/Duration

i. Moderate: 5-6/10, 5x/wk, 30-60 min/session (≥150 min/wk)

ii. Vigorous: 7-8/10, 3x/wk, 20-30 min/session (≥75 min/wk)

iii. Can be accrued in 10-min bouts

m. Prevention of Chronic Disease: Resistance Ex Dose: Frequency/Intensity/Duration

i. Moderate: 5-6/10, 2x/wk, 8-10 Ex, 8-12 reps


15

ii. Vigorous: 7-8/10, 2x/wk, 8-10 Ex, 8-12 reps

iii. Type: Progressive weight training or weight bearing Ex

n. Prevention of Chronic Disease: Flexibility Exercises: Major Muscle Groups

i. Moderate Intensity: 5-6/10

ii. Duration: 60 seconds/exercise

iii. Frequency: 2x/wk

o. Prevention of Chronic Disease: Neuromuscular Fitness - Balance/agility/coordination

i. Neuromuscular Fitness: Balance/agility/coordination

ii. Moderate Intensity: 5-6/10

iii. Frequency: 2x/wk

iv. Balance Exercises: Progressively difficult postures and gradually reduce base of

support

p. Increasing Exercise Dose in Neurodegenerative Disease: Innovative Strategies

q. Tandem Biking in PD: Augmented (or forced) Exercise (Alberts 2010, Rigdel 2009)

i. Forced exercise via tandem biking facilitates increased quantity of pedaling (higher rate)

and greater consistency (quality of pedaling).

ii. People with PD have slowed motor function making it difficult to sustain higher pace and

consistency to achieve aerobic exercise that meets the Surgeon General's Guidelines

r. Innovative Interventions & Programs

s. Considerations for Exercise Recommendations in People with MS

i. Core body temperature

ii. Exercise has been reported to trigger symptom exacerbation in more than 40% of

individuals with MS

iii. Effects normalized within 30-60 minutes after termination in most

iv. Resistance training is not accompanied by the same increase in core body temperature

as endurance training

t. Recommendations: Strengthening Exercises in MS

i. Mode

ii. Initial phase – machines, elastic bands (i.e. Theraband ®), use of body weight as load

iii. 4-8 exercises, whole body program

iv. LE exercises priority

v. Intensity

vi. 8-15 repetition maximum, 1-3 sets


16

vii. Rest periods between sets and exercises (2-4 minutes)

viii. Frequency

ix. 2-3 days per week

u. Aerobic Exercise Recommendations in MS

i. Mode

a. Bicycle ergometry

b. Arm-leg ergometry

c. Aquatic exercise

d. Treadmill walking

ii. Intensity -initial training intensity 50-70% VO2 max corresponding to 60-80% of MHR

iii. Duration - 10-40 minutes

iv. Frequency - 2-3 sessions per week, progress by increasing training duration or adding

an additional day

v. Combined Training Recommendations

i. Equal proportions of resistance- and endurance training should be performed on

alternate days

ii. Frequency

iii. 4 days/week – 2 resistance and 2 endurance

w. Summary: Exercise Recommendations

i. Exercise programs should be developed and monitored by a professional

ii. Consideration disease effect on exercise response

iii. Design exercise programs to target neuroprotective mechanisms

iv. Innovative strategies

v. Creative programs

vi. Supportive environment

vii. Focus on increasing self-efficacy

viii. Educate patients

Part 4: Innovative Exercise Approaches to Target Neuroprotective Effects of Exercise in adults with neurodegenerative disease

a. Clinic-based vs. community-based implementation

b. Model programs


17

References 1. Ahlskog EJ. Does vigorous exercise have a neuroprotective effect in Parkinsons disease? Neurology 2011, 77: 288-294. 2. Ahlskog JE, Geda YE, Graff-Radford NR, et al., Physical exercise as a preventive or disease-modifying treatment of dementia and brain-aging. Mayo Clin Proc. 2011, 86:876-884. 3. 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: 177-86. 4. Alexander NB, Dengel DR, Olson RJ and Krajewski KM. Oxygen-uptake (VO2) kinetics and functional mobility performance in impaired older adults. J Gerontol A Biol Sci Med Sci 2003; 58: 734-349. 5. Angevaren M, Vanhees L, Wendel-Vos W, Verhaar HJ, Aufdemkampe G, Aleman A, et al. Intensity, but not duration, of physical activities is related to cognitive function. Eur J Cardiovasc Prev Rehabil. 2007; 14: 825-30. 6. Baker LD, Frank LL, Foster-Schubert K, Green PS, Wilkinson CW, McTiernan A, et al. Effects of aerobic exercise on mild cognitive impairment: a controlled trial. Arch Neurol. 67: 71-9. 7. Beckerman H, de Groot V, Scholten MA, Kempen JC, Lankhorst GJ. Physical activity behavior of people with multiple sclerosis: understanding how they can become more physically active. Physical therapy. 2010; 90: 1001-13. 8. Bixby WR, Spalding TW, Haufler AJ, Deeny SP, Mahlow PT, Zimmerman JB, et al. The unique relation of physical activity to executive function in older men and women. Medicine and science in sports and exercise. 2007; 39: 1408-16. 9. Billinger SA, Vidoni ED, Honea RA, et al. Cardiorespiratory response to exercise testing in individuals with Alzheimer's disease. Arch Phys Med Rehabil, 2011; 92: 2000-05. 10. Blankevoort CG, van Heuvelen MJ, Boersma F, Luning H, de Jong J, Scherder EJ. Review of Effects of Physical Activity on Strength, Balance, Mobility and ADL Performance in Elderly Subjects with Dementia. Dement Geriatr Cogn Disord. 2010; 30: 392-402. 11.Bugg JM, Head D. Exercise moderates age-related atrophy of the medial temporal lobe. Neurobiology of aging. 2011; 32(3): 506-14. 12. Burns JM, Anderson HS, Smith HJ, Donnelly JE. Cardiorespiratory fitness in early-stage Alzheimer disease. Alzheimer Dis Assoc Disord, 2008; 22:39-46. 13. Burns JM, Cronk BB, Anderson HS, et al. Cardiorespiratory fitness and brain atrophy in early Alzheimer disease. Neurology, 2008; 71: 210-216. 14. Brown TR, Kraft GH. Exercise and rehabilitation for individuals with multiple sclerosis. Phys Med Rehabil. Clin N Am 2005; 16: 513-555. 15. Cassilhas, R. C., Viana, V. a R., Grassmann, V., Santos, R. T., Santos, R. F., Tufik, S., & Mello, M. T. (2007). The impact of resistance exercise on the cognitive function of the elderly. Medicine and science in sports and exercise, 39:1401–7. 16. Clarkson-Smith L, Hartley AA. Relationships between physical exercise and cognitive abilities in older adults. Psychology and aging. 1989; 4:183-9. 17. Chodzko-Zajko WJ, Proctor DN, Fiatarone Singh MA, Minson CT, Nigg CR, Salem GJ, et al. American College of Sports Medicine position stand. Exercise and physical activity for older adults. Medicine and science in sports and exercise. 2009; 41: 1510-30.


18

18. Colcombe SJ, Erickson KI, Scalf PE, Kim JS, Prakash R, McAuley E, et al. Aerobic exercise training increases brain volume in aging humans. J Gerontol A Biol Sci Med Sci. 2006; 61:1166-70. 19. Colcombe SJ et al., Cardiovascular fitness, cortical plasticity and aging. Proceedings of the National academy of Sciences. 2004; 101: 3316-21. 20. Colcombe, S. J., Erickson, K. I., Scalf, P. E., Kim, J. S., Prakash, R., Mcauley, E., Elavsky, S., et al. (2006). Brain Volume in Aging Humans, 61, 1166–70. 21. Cotman CW, Berchtold NC. Physical Activity and the maintenance of cognition: Learning from animal models. Alzheimer’s and Dementia. 2007; 3: 30-37. 22. Craft S. Insulin resistance and cognitive impairment: a view through the prism of epidemiology. Archives of neurology. 2005; 62: 1043-4. 23. Craft S. Insulin resistance syndrome and Alzheimer disease: pathophysiologic mechanisms and therapeutic implications. Alzheimer disease and associated disorders. 2006; 20: 298-301. 24. Dalgas U, Stenager E, Ingemann-Hansen T. Multiple sclerosis and physical exercise: recommendations for the application of resistance-, endurance-, and combined training. Multiple Sclerosis. 2008; 14: 36-53. 25. Dibble LE, Addison O and Papa E. The effects of exercise on balance in persons with Parkinson's disease: a systematic review across the disability spectrum Journal of neurologic physical therapy: JNPT. 2009; 33: 14-26. 26. Ellis T, Cavanaugh JT, Earhart GM, Ford MP, Foreman KB, Fredman L, et al. Factors associated with exercise behavior in people with Parkinson disease. Physical therapy 2011; 91: 1838-48. 27. Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock l, et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci USA. 2011; 108: 3017-22. 28. Erickson KI, Prakash RS, Voss MW, Chaddock L, Hu L, Morris KS, et al. Aerobic fitness is associated with hippocampal volume in elderly humans. Hippocampus. 2009; 19: 1030-9. 29. Erickson KI, Kramer AF. Aerobic exercise effects on cognitive and neural plasticity in older adults. British journal of sports medicine. 2009; 43: 22-4. 30. Fabel K, Kempermann G. Physical Activity and the Regulation of Neurogenesis in the Adult and Aging Brain. Neuromol Med, 2008; 10: 59-66. 31. Fisher BE, Wu AD, Salem GJ, Song J, Lin CH, Yip J, et al. The effect of exercise training in improving motor performance and corticomotor excitability in people with early Parkinson's disease Archives of physical medicine and rehabilitation 2008; 89: 1221-9. 32. Foster et al., Exercise- induced cognitive plasticity, implications for mild cognitive impairment and Alzheimer’s disease. Frontiers in Neurology, 2011; 28: 1-15. 33. Garber CE, Blissmer B, Deschenes MR, Franklin BA, Lamonte MJ, Lee IM, et al. American College of Sports Medicine position stand. Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: guidance for prescribing exercise. Medicine and science in sports and exercise. 2011; 43(7): 1334-59. 34. Geda YE, Roberts RO, Knopman DS, Christianson TJ, Pankratz VS, Ivnik RJ, et al. Physical exercise, aging, and mild cognitive impairment: a population-based study. Archives of neurology. 2010; 67: 80-6.


19

35. Heyn P, Abreu BC, Ottenbacher KJ. The effects of exercise training on elderly persons with cognitive impairment and dementia: a meta-analysis. Archives of physical medicine and rehabilitation. 2004; 85: 1694-704. 36. Hill RD, Storandt M, Malley M. The impact of long-term exercise training on psychological function in older adults. Journal of gerontology. 1993; 48: 12-7. 37. Hillman et al., Be Smart, exercise your heart: exercise effects on brain and cognition. Perspectives, 2008;9: 58-65. 38. Hirsch MA and Farley BG. Exercise and neuroplasticity in persons living with Parkinson's disease European journal of physical and rehabilitation medicine 2009; 45: 215-29. 39. Hirsch MA, Iyer SS, Englert D, Sanjak M. Promoting exercise in Parkinson's disease through community-based participatory research. Neurodegener Dis Manag. 2011; 1: 365-77. 40. 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. Movement disorders : official journal of the Movement Disorder Society. 2007; 22: 451-60. 41. Kramer AF, Erickson KI. Capitalizing on cortical plasticity: influence of physical activity on cognition and brain function. Trends in Cognitive Science. 2007; 11: 342-348. 42. Kramer AF, Erickson KI. Effects of physical activity on cognition, well-being, and brain: Human Interventions. Alzheimer’s and Dementia. 2007; 3: 45-51. 43. Katzel L, Sorkin J, Macko R, Smith B, Ivey F, Shulman L. Repeatability of aerobic capacity measurements in Parkinson disease. Medicine & Science in Sports & Exercise. 2011, 43: 2381-87. 44. Karstoft K, Winding K, Knudsen SH, Nielsen JS, Thomsen C, Pedersen BK, et al. The Effects of Free-Living Interval-Walking Training on Glycemic Control, Body Composition, and Physical Fitness in Type 2 Diabetes Patients: A randomized, controlled trial. Diabetes Care. 2012. 45. Kwak YS, Um SY, Son TG, Kim DJ. Effect of regular exercise on senile dementia patients. Int J Sports Med. 2008; 29: 471-4. 46. Kwakkel G, de Goede CJ, van Wegen EE. Impact of physical therapy for Parkinson's disease: a critical review of the literature. Parkinsonism Relat Disord. 2007; 13 Suppl 3: S478-87. 47. Larson EB, Wang L, Bowen JD, McCormick WC, Teri L, Crane P, et al. Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann Intern Med. 2006; 144: 73-81. 48. Liu-Ambrose T, Nagamatsu LS, Graf P, Beattie BL, Ashe MC, Handy TC. Resistance training and executive functions: a 12-month randomized controlled trial. Arch Intern Med. 2010; 170: 170-8. 49. McGough EL, Kelly VE, Logsdon RG, McCurry SM, Cochrane BB, Engel JM, et al. Associations between physical performance and executive function in older adults with mild cognitive impairment: gait speed and the timed "up & go" test. Physical therapy. 2011; 91: 1198-207. 50. Mehrholz J, Friis R, Kugler J, Twork S, Storch A, Pohl M. Treadmill training for patients with Parkinson's disease. Cochrane Database Syst Rev. 2010; (1): CD007830. 51. Middleton L, Kirkland S, Rockwood K. Prevention of CIND by physical activity: different impact on VCI-ND compared with MCI. J Neurol Sci. 2008; 269: 80-4. 52. Motl RW, Goldman M. Physical inactivity, neurological disability, and cardiorespiratory fitness in multiple sclerosis. Acta neurologica Scandinavica. 2011; 123: 98-104. 53. Motl RW, Pilutti LA. The benefits of exercise training in multiple sclerosis. Nat Rev Neurol. 2012; 8: 487-97.


20

54. Motl RW, Suh Y, Dlugonski D, Weikert M, Agiovlasitis S, Fernhall B, et al. Oxygen cost of treadmill and over-ground walking in mildly disabled persons with multiple sclerosis. Neurol Sci. 2011; 32: 255-62. 55. Mostert S, Kesselring J. Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis. Mult Scler. 2002; 8: 161-8. 56. Nakamura T, Hirayama M, Yamashita F, Uchida K, Hama T, Watanabe H, et al. Lowered cardiac sympathetic nerve performance in response to exercise in Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society. 2010; 25: 1183-9. 57. Pantano, P., Mainero, C., & Caramia, F. (2006). Functional brain reorganization in multiple sclerosis: evidence from fMRI studies. Journal of neuroimaging  : official journal of the American Society of Neuroimaging, 16, 104–14. 58. Petajan JH, Gappmaier E, White AT, Spencer MK, Mino L, Hicks RW. Impact of aerobic training on fitness and quality of life in multiple sclerosis. Annals of neurology. 1996; 39: 432-41. 59. Petzinger GM, Fisher BE, Van Leeuwen JE, Vukovic M, Akopian G, Meshul CK, et al. Enhancing neuroplasticity in the basal ganglia: the role of exercise in Parkinson's disease Movement disorders. 2010; 25 Suppl 1: S141-5. 60. Prakash, R. S., Snook, E. M., Erickson, K. I., Colcombe, S. J., Voss, M. W., Motl, R. W., & Kramer, A. F. (2007). Cardiorespiratory fitness: A predictor of cortical plasticity in multiple sclerosis. NeuroImage, 34, 1238–44. 70. Prakash, R. S., Snook, E. M., Motl, R. W., & Kramer, A. F. (2010). Aerobic fitness is associated with gray matter volume and white matter integrity in multiple sclerosis. Brain research, 1341, 41–51. 71. Protas EJ, Stanley RK, Jankovic J. 1997. Parkinson’s Disease . In ACSM’s Exercise Management for Person’s with Chronic Diseases and Disabilities, ed. J.L. Durstine, Champaign: Human Kinetics 72. Ridgel AL, Vitek JL, Alberts JL. Forced, not voluntary, exercise improves motor function in Parkinson's disease patients. Neurorehabil Neural Repair. 2009; 23: 600-8. 73. Rigdel AL, Muller MD, Kim C, et al., Acute effects of passive leg cycling on upper extremity tremor and bradykinesia in Parkinson's disease. The Physician and Spots Medicine. 2011, 39: 83-93. 74. Rietberg M, Brooks D, Uitdehaag B, Kwakkel G. Exercise therapy for multiple sclerosis. Cochrane Database Syst Rec. 2005; CD003980. 75. Rimmer JH, Schiller W, Chen MD. Effects of disability-associated low energy expenditure deconditioning syndrome. Exerc Sport Sci Rev. 2012, 40: 22-29. 76. Rimmer JH, Marques AC. Physical activity for people with disabilities. Lancet. 2012, 380 (9838): 193-195. 77. Rimmer JH, Chen MD, McCubbin JA, Drum C and Peterson J. Exercise intervention research on persons with disabilities: what we know and where we need to go American journal of physical medicine & rehabilitation. 2010; 89: 249-63. 78. Rimmer JH, Hsieh K, Graham BC, Gerber BS and Gray-Stanley JA. Barrier removal in increasing physical activity levels in obese African American women with disabilities Journal of women's health. 2010; 19: 1869-76.


21

79. Rovio S, Kareholt I, Helkala EL, Viitanen M, Winblad B, Tuomilehto J, et al. Leisure-time physical activity at midlife and the risk of dementia and Alzheimer's disease. Lancet Neurol. 2005; 4: 705-11. 80. Roach KE, Tappen RM, Kirk-Sanchez N, Williams CL, Loewenstein D. A randomized controlled trial of an activity specific exercise program for individuals with Alzheimer disease in long-term care settings. Journal of geriatric physical therapy. 2011; 34: 50-6. 81. Smiley-Oyen AL, Lowry KA, Francois SJ, Kohut ML, Ekkekakis P. Exercise, fitness, and neurocognitive function in older adults: the "selective improvement" and "cardiovascular fitness" hypotheses. Ann Behav Med. 2008; 36: 280-291. 82. Speelman AD, van de Warrenburg BP, Nimwegen van Nimwegen M, et al., How might physical activity benefit patients with Parkinson disease. Nat. Rev. Neurol. doi:10.1038/nmeurol.2011.107. 83. Smith RM, ey-Steel M, Fulcher G, Longley WA. Symptom change with exercise is a phenomenon for people with multiple sclerosis. Arch Phys Med Rehabil. 2006; 87: 723-27. 84. Schenkman M, Hall DA, Baron AE, Schwartz RS, Mettler P, Kohrt WM. Exercise for people in early- or mid-stage Parkinson disease: a 16-month randomized controlled trial. Physical therapy. 2012; 92: 1395-410. 85. Seifert, T., Brassard, P., Wissenberg, M., Rasmussen, P., Nordby, P., Stallknecht, B., Adser, H., et al. (2010). Endurance training enhances BDNF release from the human brain. American journal of physiology. Regulatory, integrative 86. Tajiri N, Yasuhara T, Shingo T, Kondo A, Yuan W, Kadota T, et al. Exercise exerts neuroprotective effects on Parkinson's disease model of rats. Brain Res. 2010; 1310: 200-207. 87. Teri L, Gibbons LE, McCurry SM, Logsdon RG, Buchner DM, Barlow WE, et al. Exercise plus behavioral management in patients with Alzheimer disease: a randomized controlled trial. JAMA. 2003; 290: 2015-22. 88. Teri L, Logsdon RG, McCurry SM. Exercise interventions for dementia and cognitive impairment: the Seattle Protocols. The journal of nutrition, health & aging. 2008; 12: 391-4. 89. Thacker EL, Chen H, Patel AV, McCullough ML, Calle EE, Thun MJ, et al. Recreational physical activity and risk of Parkinson's disease. Movement disorders. 2008; 23(1): 69-74. 90. Umpierre D, Ribeiro PA, Kramer CK, Leitao CB, Zucatti AT, Azevedo MJ, et al. Physical activity advice only or structured exercise training and association with HbA1c levels in type 2 diabetes: a systematic review and meta-analysis. JAMA. 2011; 305: 1790-9. 91. Van Praag H. Neurogenesis and Exercise: Past and Future Directions. Neuromol Med. 2008; 10:128-140. 92. White LJ, McCoy SC, Casteliano V, Gutierrez G, Stevens JE, Walter GA et al. Resistance training improves strength and functional capacity in persons with multiple sclerosis. Mult Scler. 2004; 10: 668-674. 93. Whaley MH, Brubaker PH, Otto RM, Armstrong LE. ACSM's guidelines for exercise testing and prescription. 7th ed. Philadelphia, Pa.: Lippincott Williams & Wilkins; 2006. 94. van Gelder BM, Tijhuis MA, Kalmijn S, Giampaoli S, Nissinen A, Kromhout D. Physical activity in relation to cognitive decline in elderly men: the FINE Study. Neurology. 2004; 63: 2316-21. 95. Voss, M. W., Prakash, R. S., Erickson, K. I., Basak, C., Chaddock, L., Kim, J. S., Alves, H., et al. (2010). Plasticity of brain networks in a randomized intervention trial of exercise training in older adults. Frontiers in aging neuroscience, 2, 1–17.


22

96. Vuckovic MG, Li Q, Fisher B, Nacca A, Leahy RM, Walsh JP, et al. Exercise elevates dopamine D2 receptor in a mouse model of Parkinson's disease: in vivo imaging with [(1)(8)F]fallypride Movement Disorders: 2010; 25: 2777-84. 97. Waldstein SR. The relation of hypertension to cognitive function. Current Directions in Psychological Science, 2003; 12: 8-12. 98. White, L. J., & Castellano, V. Exercise and Brain Health –Implications for Multiple Sclerosis: Part 1 – Neuronal Growth Factors, Sports Med. 2008; 38, 91–100. 100. White, L. J., & Castellano, V. (2008). Exercise and Brain Health – Implications for Multiple Sclerosis: Part 2 – Immune Factors and Stress Hormones. Sports Med. 2008; 38:179-86. 101. Xu Q, Park Y, Huang X, Hollenbeck A, Blair A, Schatzkin A, et al. Physical activities and future risk of Parkinson disease. Neurology. 2010; 75: 341-8. 102. Yaffe K, Barnes D, Nevitt M, Lui LY, Covinsky K. A prospective study of physical activity and cognitive decline in elderly women: women who walk. Archives of internal medicine. 2001; 161: 1703-8. 103. Yaffe K, Alkakanaya A, Lindquist K, Simonsick EM, et al. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA, 2004; 292: 2237-42. 104. Yaffe K, Lindquist K, Penninx BW, Simonsick EM, et al. Inflammatory markers and cognition in well-functioning African-American and White elders. Neurology, 2003. 61:76-80. 105. Zigmond MJ, Cameron JL, Leak RK, et al. Triggering endogenous neuroprotective processes through exercise in models of dopamine deficiency. Parkinsonism and Related Disorders, 2009, 1553:S42-S45.

exercise interventions targeting neuroplasticity and

Documents