1. EXERCISE IN Parkinson's disease: what does the data tell us about neuroprotection and neurorestoration?
AAPMR November 2014
Christina Marciniak
The Rehabilitation Institute of Chicago and Northwestern University

2. I have no relevant disclosures.

3. Objectives
Discuss preclinical evidence for exercise as neuro-protection in PD
Review retrospective human studies suggesting exercise is neuro-protective in PD
Discuss human studies evaluating exercise effects in neuro-restoration in PD
Because PD is a progressive disorder, early diagnosis and treatment intervention with neuroprotective therapies to slow or prevent further degeneration and to promote neuronal repair are current goals in the management of PD
There is experimental evidence for the role of exercise in in restoration of neural pathways as well as its potential role in presymptomatic persons as a neuroprotective mechanisms. We are all very well aware of the effects of inactivity on function in a number of patient populations, and specifically in PD there are animal studies that have documented that inactivity is pro-degenerative.
Review these studies quickly for you and Recent Advances in Basic
Neuroscience in Exercise and PD
Animal models with PD show response to exercise
varies with phase of disease 1.  
Preclinical phase —
Neuroprotection 2.
Early/Moderate phase —
Neurorepair 3.
Late phase —
Adaptation/Compensation
Therapy impacting underlying neurodegenerative mechanisms in order to halt or slow progression of PD and to promote the preservation, rescue, or restoration of lost neurons

4. Cumulative RCT/CCTs of Physical Therapy in PD
Cumulative number of randomized and controlled clinical trials on the efficacy of physical therapy in PD Parkinson Disease
Keus et al. Physical Therapy in Parkinson’s Disease: Evolution and Future Challenges.2009;Movement Disorders:24(1)

5. Exercise protects against toxin induced PD in Animal Models.
6 hydroxy domamine. aMPTP causes a specific loss of substantia nigra neurons that recapitulate the dopaminergic loss seen in idiopathic CP. It is MPP is metabolites interfere with dopamine transporter and subsequently the eel transport chain of the mitochondria., subsequent generation of free radicals. By one week post administration, there is a significant loss of DA neurons and There are now multiple animal studies documenting the effects of exercise in experimentally induced PD. Animals modes use MPTP or 6=OHDA, which interfere tight mitochondrial electron transport, and create neuronal damage as fee radical s are generated.
Exercise has been shown to reduce free radical production, protect neurons due to purgation of trophic factors and also modulate excitatory brain amino acids. Exercise has even been shown to have a protective affect the olfactory bulb cells in animal models of PD
Petzinger GM et al. Effects of treadmill exercise on dopaminergic transmission in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of basal ganglia injury. L Neurosci 2007; 27:

6. Duration/Intensity of exercise determine toxin effects.
3 months of exercise, but not 1 or 2 months prior to MPTP administration provided complete protection from DA loss in mice.
Protein changes related to energy regulation, cellular metabolism, cytoskeleton, intracellular signaling even
Gerecke. Brain Research 2010
Mice running unrestricted, but limited in distance or time lost DA cells
Faherty. Brain Research 2005
Kimberly Gereck studied the duration of exercise necessary for DA neuroprotection. Mice were allowed to run for either 1, 2 or 3months prior to treatment with either saline or MPTP. DA neuron in the substantia nigra were quantified and it was found that mice running unrestricted for 1 or 2 months lost significant number of neurons as compared to saline, however 3 months provided complete protection. Free running was 7.5 kilometers daily with corresponds to 18,000 wheel revolutions, 6000 or 12,000 wheel revolutions.
To determine intensity, mice were restricted in their running to either 1/3 or 2/3 of the full running group for 3 months prior to treatment. The 2;/3 group had partial protection. Changes were demonstrated in cellular metabolism intracellular signally events, cell cytoskeleton, and energy regulation MPTP or methyl phenyl tetrahydropyridine . In another study, 3 months of exercise, but not 1 or 2 months prior to the administration of the neurotoxin MPTP completed protected DA loss in the mice.
However, it running was continued, but was restricted in either distance or time, DA loss was found.
Thus there are important dose effects of exercise in the animal models, similar to the epidemiologic studies that I reported.

7. Exercise elevates dopamine D2 receptor in a mouse model of Parkinson's disease. in vivo Dec 15;25(16): n California, Los Angeles, California, USA.
dopamine D2 receptor (DA-D2R) expression within the basal ganglia of MPTP mice subjected to intensive treadmill exercise.
Importantly, findings from this study support the rationale for using PET imaging with [¹⁸F]fallypride to examine DA-D2R changes in individuals with Parkinson's Disease (PD) undergoing high-intensity treadmill training.
Marta G. Vučković, et al.
Movement Disorders. 2010
December 15;25(16):

8. Exercise results in Enhanced Connectivity
Dopamine plays an improtant role in modulaing synapes and with PD, connections between the cortex and BG are dyrupted. There synaptic connections occur on special outcroppings of cells called spine. With doamin loss, there is los of these spine connections. Treatdmill results in return in the number of spine despite no increase in the number os substantia nigra neurons

9. Exercise appears neuroprotective in retrospective human studies.
Moderate or vigorous levels of physical activity are associated with lower risk of developing PD
Chen H et al. Physical activity and the risk of Parkinson’s disease. Neurology 2005; 64:664-9.
Regular exercise delays the appearance of parkinsonian features in persons already diagnosed with PD.
Tsia CH et al. Environmental risk factors of young-onset Parkinson’s disease: a case-control study: Clin Neurol Neurosurg 2002;104:328-33
Chen prospectively followed 48,574 men and women who provided information on physical activity in 1986 and early adulthood. Greater baseline physical activity was associated with lower PD risk. Strenuous exercise in early adult life was also inversely related to PD risk in men. In women physical activity at baseline e was not found to be related though strenuous exercise in early adulthood trended to be inversely related to PD risk later.
TSIA look at PD patients with young onsent, before age 40 in a case control fashion. They wound well water drinking and head injury were risk factors for Yong onset PD. Regular exercise, defined at least 30 minutes, 3 times a week, was associated with a lower risk.
Tsia

10. Exercise throughout adulthood decreases PD.
View larger version (11K): [in this window] [in a new window]   Figure 1 Changes of physical activities in relation to risk of Parkinson disease (PD)Odds ratios (OR) and 95% confidence intervals (CI) of PD after 2000 according to changes of moderate to vigorous physical activities between ages and in the past 10 years as reported at the risk factor survey in The analysis adjusted for age at risk factors survey, gender, race, education levels, smoking status, and coffee consumption.
Xu evaluated physical activity in PD in over 200,000 persons participating an an NIH-AARP study of Diet and Health. Information on physical activity was collected over 4 age periods 15-18, 19-29, and past 10 years, and then they looked at risk for physician diagnosed PD. A significant dose response relationship was observed, with odds ratio between the post lowest levels of activity at .62 vs. those exercising at Among thus with consistent and frequent activity both at and past 10 years, they had a 40 per cent lower risk than those with low exercise levels at these two time periods.
Odds Ratio 0.40
Xu, Q. et al. Neurology 2010;75:

11. Acutely, forced exercise changes Cortical activation
Figure 6.
Cortical and subcortical activation maps across subjects. Highlighted areas indicate areas in the brain where increased blood flow, or cortical activation is present with hand movement tasks during scanning. This figure is an average of nine patients with Parkinsons disease (PD) under three conditions: on antiparkinsonian medication, off antiparkinsonian medication, and 3-h post forced exercise (FE) while off antiparkinsonian medication. The pattern of cortical and subcortical activation was similar while patients were on medication and following FE while off medications.
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Exerc Sport Sci Rev. 2011;39(4):  © 2011 American College of Sports Medicine The effects of acute FE on brain activation pattern were studied in nine mild-to-moderate patients with PD, not part of the long-term study, using a magnetic resonance imaging (MRI) protocol including whole brain T1-weighted anatomic images and a set of fMRI scans. Subjects were scanned under three conditions: 1) off meds, 2) on meds, and 3) after FE while off meds. The order of scan sessions was randomized across subjects. Each session was separated by 5–7 d. On the FE day, subjects performed 40 min of FE, showered (to maintain blinding of the neurologist), rested, and ate a light snack and were evaluated 3 h later. After the UPDRS-III, subjects were transported by wheelchair to the scanner. During scanning, subjects performed a constant or sinusoidal force-tracking task, which we have used previously. All subjects were fitted for a bite bar to restrict head motion during scanning.igure 6.
igure 6 shows activation maps averaged across subjects for two axial slices (showing subcortical and cortical regions) in Talairach space, displayed on averaged T1 anatomic image. Regions of interest (ROI) were drawn in bilateral putamen, globus pallidus, thalamus, primary motor, and supplementary motor area. The effect of FE (vs off medication) was compared with the effect of medication by examining the percent signal change in the side contralateral to the task, as shown in Table 3. In all five regions, strong correlations were observed, indicating a similar change in BOLD MRI response for FE and medication. Blinded UPDRS-III ratings in these same patients decreased 35% and 32% after FE and on medication compared with off medication, respectively. Imaging data indicate a significant correlation between FE and medication for regions in the basal ganglia and cortex. These results indicate that FE and medication utilize similar pathways to produce symptomatic relief. We are unaware of any other data that demonstrates that exercise in PD leads to an increase in cortical and subcortical activation.
(Enlarge Image)
Exerc Sport Sci Rev. 2011;39(4):  © 2011 American College of Sports Medicine
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Figure 5.
Center of pressure for all dexterity trials for patients in the forced exercise (FE) (x) and voluntary exercise (VE) (o) groups at baseline, end of training (EOT), and EOT + 4 wk. The upper limb performs the manipulating action, whereas the lower limb acts to stabilize the device. Ellipses define the area of spread to encompass 95% of the data. Forced exercise resulted in significantly less spread in center of pressure (COP) than VE. Smaller ellipses indicate less variability in COP and digit placement. (Reprinted from (22). Copyright © 2009 Society for Neuroscience. Used with permission.)

12. Parkinson’s and Exercise
After diagnosis, persons with PD decrease their physical activity levels. Only 12-15% are referred to physiotherapy.
Thacker EL et al. Recreational physical activity and risk of Parkinson’s disease. Movement Disorders 2008; 23:69-74
Only 7-57% report being treated by a physical therapist, though there are large differences in utilization.
Nijkrake MJ et al. Allied healthcare in Parkinson’s disease: referral, consultation, and professional expertise. Movement Disorders 2009; 24:282-6.
THACKER 2008.
Researchers investigated an association between recreational physical activity and Parkinson’s disease risk.
The authors prospectively followed 143,325 participants in the Cancer Prevention Study II Nutrition Cohort from 1992 to 2001 (mean age at baseline = 63).
Recreational physical activity was estimated at baseline from the reported number of hours per week on average spent performing light intensity activities (walking, dancing) and moderate to vigorous intensity activities (jogging/running, lap swimming, tennis/racquetball, bicycling/stationary bike, aerobics/calisthenics).
Incident cases of PD (n = 413) were confirmed by treating physicians and medical record review.

13. Neurorestoration: Are there Exercise effects in PD patients?
High Intensity exercise can normalize
Corticomotor excitability in early PD
Fisher, Archives PMR 2008
Subjects with PD Hoehn and Yahr Stage 1-2 randomized to 3 groups
Zero intensity exercise (education)
Low intensity exercise (50%) – 24 sessions over 8 weeks
High intensity exercise (75%)– 24 treadmill training over 8 weeks
High-intensity group subjects: Clinical outcomes: Post-exercise increases in:
Increases in gait speed, step and strike length
Hip and ankle joint excursion during self-selected fast gait
Improved weight distribution during sit-to stand tasks
Outcome: Corticomotor excitability measured by
Transcutaneous Mag Stim Silent Period
Beth Fisher and colleagues evaluated the effects high intensity exercise on cortico-motor excitability as well as PD related impairments. PD patients Hoehn and Yahr stage 1 or 2 were randomized to either a control group which received group education or 24 exercises sessions using body weight support. Subjects in the high intensity group goal group was to exercise at 3 met level with proper gait mechanics for 45 minutes or at 75% of the age appropriate maximal heart rate. The low intensity group exercise group received traditional PD exercise program including active ROM, stretching, balance, resistance training gait training with Mets estimated at 50% of the maximal heart rate. USC study. Gait parameters and PD specific measures such as Unified Parkinson disease rating scale were evaluated.
Corticomotor excitability was measured using transcranial magnetic stim silent period. In PD patients, the silent period With cortical stimulation, applied over the motor cortex and recording at the contralateral flexor digitorum indicis, If the target muscle is preactivated, the PMS pulse induces a characteristic transient period of electromyographic silence called the . Silent periods Studies in PD patients had demonstrated higher corticomotor excitability, as compared to controls.

14. Cortical Silent Period effects With High intensity exercise
Forced group improved their unified Parkinson disease rating motor cores 35 percent while the control group did not change. Additionally, as demonstrated on this slide, the cortical spinal period consistently lengthening the high intensity group, which this effect was not seen in the other groups which suggests that high intensity exercise may induce activity dependent neuroplasticity in corticomotor excitability.
All subjects showed improved gait velocity more evident in the high intensity group.
In anther study looking at high intensity exercise in PD, tandem bike training was used to force patients to exercise at a high rated. Control group pedaled at their preferred speed but the aerobic intensity was kept constant, and with both groups exercised at percent of their individualized training heart rate. Subject exercised at 30 percent greater than their preferred rate.
Both groups improved their aerobic fitness.
Thirty people with PD, within 3 years of
diagnosis with Hoehn and Yahr stage 1 or 2.
Interventions: Subjects were randomized to high-intensity
exercise using body weight–supported treadmill training, low intensity
exercise, or a zero-intensity education group. Subjects
in the 2 exercise groups completed 24 exercise sessions over 8
weeks. Subjects in the zero-intensity group completed 6 education
classes over 8 weeks.
Main Outcome Measures: Unified Parkinson’s Disease
Rating Scales (UPDRS), biomechanics analysis of self-selected
and fast walking and sit-to-stand tasks; corticomotor excitability
was assessed with cortical silent period (CSP) durations in
response to single-pulse TMS.
Results: A small improvement in total and motor UPDRS
was observed in all groups. High-intensity group subjects
showed post exercise increases in gait speed, step and stride
length, and hip and ankle joint excursion during self-selected
and fast gait and improved weight distribution during sit-to stand
tasks. Improvements in gait and sit-to-stand measures
were not consistently observed in low- and zero-intensity
groups. The high-intensity group showed lengthening in CSP.
Conclusions: The findings suggest the dose-dependent benefits
of exercise and that high-intensity exercise can normalize
corticomotor excitability in early PD.
Key Words: Basal ganglia; Central nervous In this study by Fisher in archives PMR, subject within 3 years of PD at H and Y stages 1 or 2 – were randomized to high intensity exercise with body weight supported treadmill, a lower insentinsy exercise group or a zero intensity where subjects received education classes.
Measured UPDRS scales, gait measures, as well as corticomotor excitability assessed by measuring the cortical silent period duration in response to pulsed Transcutaneous magnetic stimulation. The pulse with delivered over the motor cortex and surface EMG recorded over the contralateral muscle.
Clinical measures of gait speed, step and stride length and hip and ankle joint excursion were found with self-selected and fast gait. Every subject in the high intensity g group showed lengthening of the cortical silent period., suggesting that exercise can normalize corticomotor excitability in PD patients, but these improvements were not consistently found in the zero or low intensity group.
Every subject in the high intensity group shoulder lengthening of the cortical silent period.

15. Forced Exercise and PD: Rate vs REsistanCe
Tandem bike used to force patients to exercise 30 % greater than preferred rate
Control group exercised at preferred rate
Ridgel, Neurorehab and Neural Repair 2009
Jay L. Alberts, Susan M. Linder, Amanda L. Penko, Mark J. Lowe1, Micheal Phillip Exerc Sport Sci Rev. 2011;39(4):  
Ten
patients with mild to moderate PD were randomly assigned to complete 8 weeks of FE or VE. 60 minutes total. With the assistance of a trainer, patients
in the FE group pedaled at a rate 30% greater than their preferred voluntary rate, whereas patients in the VE group pedaled at their preferred
rate. Aerobic intensity for both groups was identical, 60% to 80% of their individualized training heart rate. Results. Aerobic fitness
improved for both groups. Following FE, Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores improved 35%, whereas
patients completing VE did not exhibit any improvement. The control and coordination of grasping forces during the performance of a
functional bimanual dexterity task improved significantly for patients in the FE group, whereas no changes in motor performance were
observed following VE. Improvements in clinical measures of rigidity and bradykinesia and biomechanical measures of bimanual dexterity
were maintained 4 weeks after FE cessation. Conclusions. Aerobic fitness can be improved in PD patients following both VE and FE
interventions. However, only FE results in significant improvements in motor function and bimanual dexterity. Biomechanical data indicate
that FE leads to a shift in motor control strategy, from feedback to a greater reliance on feed forward processes, which suggests FE
may be altering central motor control processes.
Key Words: Parkinson’s disease; Exercise; Manual dexterity; Motor control; Grasping forces; Movement disorder

16. “Forced” exercise improved PD Motor Score on the UPDRS.
BOTH GROUPS IMPROVED THEIR AEROBIC CONDITIONING
The forced exercise group improved the motor scores for the unified Parksinson disease rating scores by 35% (with lower being better) while there was no change in the voluntary exercise group.

17. “Forced” cycling improves hand Fxn
Slide
In addition, measures of bimanual dexterity improved, and were maintained for 4 weeks after FE cessation. F

18. Three hours of aerobic Exercise/Day increases BDNF in persons with PD
T1 10 days, T2 30 days and T3 discharge – 28 daysTime course of BDNF serum levels in the group of patients who
underwent intensive rehabilitation treatment (black) and in the control
group (white) at time T0 (admission/visit), T1 (10 days after), T2 (20
days after), and T3 (discharge, 28 days after). *P = .017.
Thirty participants in the early stages of PD treated with rasagiline
were randomly assigned to 3 hours of rehabilitation treatment that included aerobic exercise for 28 days (Group 1) or to
not therapy (control; Group 2). BDNF serum levels were assessed at time T0 (baseline, before treatment), T1 (10 days),
T2 (20 days), and T3 (28 days). At T0 and T3, we assessed the Unified Parkinson’s Disease Rating Scale (UPDRS) III in both
groups, as well as the UPDRS II and total, Berg Balance Scale, and 6-minute walking test only in Group 1. Results . BDNF
levels significantly increased at T1 in Group 1, an increase that was maintained throughout the treatment period. At T3
compared to T0, UPDRS III scores significantly improved in Group 1 along with scores for UPDRS II, total, Berg Balance
Scale, and 6-minute walking test. Conclusions . Intensive rehabilitation treatment increases the BDNF levels and improves
PD signs in patients in the early stages of the disease. These results are in line with studies on animal models of PD and

19. National PARKINSON FOUNDATION DATA REGISTRY STUDY OF EXERCISE IN PD

20. Neuro -Protection and Neuro -Restoration
Continuous, deficit-targeted, intensive training may confer neuroprotection and thereby slow, stop or reverse the progression of the disease or promote neurorestoration through adaptation of compromised signaling pathways.
However, intensity, duration and task-specific paradigms are likely important.
Barriers PD patients encounter with exercise need to be addressed .
Does it do this by increasing GDNF or DBNF wich is believed to underlie the changes in mtor function?