Benefit of exercise and possibility of

neuro-protection with early pharmacological

treatment of PDVikki Alvarez, MD

NeurologistMovement Disorder Specialist

Center for neurological Care and Research

Exercise

• PD Diagnosis and Treatment Guidelines from the AAN

• Rx………• Exercise may improve motor function and speech

• The effectiveness of exercise interventions for people with Parkinson’s disease: meta-analysis, 14 randomized, controlled trials of exercise were identified that had a target population of PD patients

• “Exercise is of benefit to people with PD in respect of physical functioning, HRQoL, strength, balance, and gait speed,” the authors conclude.

Pilot study of qigong for Parkinson’s disease finds a significant improvement in motor symptoms.• February 28, 2009 by David Bendall • Researchers at the University of Bonn in Germany

conducted a randomized pilot study, which assigned 56 patients with Parkinson’s disease to either a qigong group or a control group. The qigong group received 90 minutes per week of qigong instruction for 2 months, followed by a 2-month pause and then 2 additional months of qigong

• Qigong or chi kung, the Chinese philosophy and practice of aligning breath, physical activity and awareness for mental, spiritual and corporeal health, as well as the development of human potential

Tai chi improves balance and mobility in people with Parkinson’s disease. Researchers at the Washington University School of Medicine in Saint Louis,

Missouri did a pilot study to examine the effects of tai chi on balance, gait and mobility in people with Parkinson’s disease. 33 individuals with Parkinson’s disease were randomly assigned to 20 hour long tai chi classes over a 10-13 week period while the [...]

Individuals with Parkinson’s disease show improvements in

physical-performance after tai chi-based exercise program.

• Researchers at the Oregon Research Institute in Eugene evaluated a tai chi based exercise pilot-program for older adults with Parkinson’s disease. 17 individuals, average age 72 with mild to moderate Parkinson’s disease were evaluated before and after a 5-day, 90 minute per day tai chi exercise program.

Participants report improvements in Tai Chi for Parkinson’s buddy pilot program.• Researchers at D’Youville College in Buffalo conducted a randomized pilot

study of a tai chi buddy program where 8 individuals with Parkinson’s disease and 7 support partners without Parkinson’s disease. All participants received a 45-minute per week session of tai chi for 12 weeks.

Yoga Used To Treat Parkinson's Disease

Targets Balance, Posture, Tremor

•Effects of tango on functional mobility in Parkinson's disease: a

preliminary study. Hackney ME, Kantorovich S, Levin R, Earhart GM. Physical Therapy, Washington University School of Medicine, St. Louis, Missouri, USA.

• Recent research has shown that dance, specifically tango, may be an appropriate and effective strategy for ameliorating functional mobility deficits in people who are frail and elderly. Individuals with Parkinson's disease (PD) experience declines in functional mobility that may be even more pronounced than those experienced by frail elderly individuals without PD. The purpose of this study was to compare the effects of two movement programs: tango classes or exerciseclasses. Nineteen subjects with PD were randomly assigned to a tango group or a group exercise class representative of the current classes offered in our geographical area for individuals with PD. Subjects completed a total of 20 tango or exercise classes and were evaluated the week before and the week following the intervention. Both groups showed significant

improvements in overall Unified Parkinson's Disease Rating Scale (UPDRS) score and nonsignificant improvements in self-reported Freezing of Gait. In addition, the tango group showed significant improvements on the Berg Balance Scale. The exercise group did not improve on this measure. Finally, the tango group showed a trend toward improvement on the Timed Up and Go test that was not observed in theexercise group.

Xbox Kinect Games to Slow Progression of Parkinson's• May 17, 2011 by James Brightman. Xbox 360 is often thought of as a core gamer's

console, but thanks to the Kinect camera, which has shipped over 10 million units so far, the reach of Microsoft's system is widening and perhaps one of the more interesting uses of the Kinect technology is a very serious one: helping people afflicted by Parkinson's disease.

• Serious games developer Red Hill Studios has created, in partnership with the UCSF School of Nursing, a custom suite of Kinect-based physical therapy games that have been specifically designed to help people with Parkinson's. The games "elicit movements and gestures that the clinical team from UCSF had shown were beneficial for improving gait and balance in people with Parkinson's disease" and ultimately this is supposed to slow the progression of the neurodegenerative disease, which affects over one million Americans. Some doctors believe that enough of the right kind of exercise can "halt progress of Parkinson's entirely."

Nintendo Wii May Enhance Parkinson's Treatment

• ScienceDaily (June 12, 2009) — The Nintendo Wii may help treat symptoms of Parkinson's disease, including depression, a Medical College of Georgia researcher says.

Parkinson's Patients Go to Wii-hab• Playing virtual sports on the Nintendo Wii, an

interactive video game console that makes players feel like they're actually playing the sport, improved the

• mood • physical function

• Neurobiol Dis. 2003 Jun;13(1):1-14.

Regulation of brain function by exercise. Sutoo D, Akiyama K.

• The effect of excercise on brain function was investigated through animal experiments. Exercise leads to increased serum calcium levels, and the calcium is transported to the brain. This in turn enhances brain dopamine synthesis through a calmodulin-dependent system, and increased dopamine levels regulate various brain functions. In epileptic mice, convulsions normalized dopamine levels and physiologic function. These findings suggest that exercise or convulsions affect brain function through calcium/calmodulin-dependent dopamine synthesis. This leads to the possibility that some symptoms of Parkinson's disease or senile dementia might be improved by exercise.

• J Neurosci Res. 2010 Feb 15;88(3):650-68.• Altered AMPA receptor expression with

treadmill exercise in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of basal ganglia injury.

• high-intensity treadmill exercise increases AMPAR subunit expression, receptor channels provide a key mechanism for regulating synaptic strength and synaptic neuroplasticity . MPTP mice suggests that exercise may also influence AMPAR trafficking and thus synaptic strength within the striatum. Finally, treadmill exercise also altered flip isoforms of GluR2 and GluR1 mRNA transcripts. These findings suggest a role for AMPARs in mediating the beneficial effects of exercise and support the idea that adaptive changes in GluR2 subunit expression may be important in modulating experience-dependent neuroplasticity of the injured basal ganglia.

• Parkinsonism Relat Disord. 2009 Dec;15 Suppl 3:S42-5.

• Triggering endogenous neuroprotective processes through exercise in models of dopamine deficiency.

• Our studies include mice or rats provided access to a running wheel and subsequently treated with MPTP (mice) or 6-hydroxydopamine (rats) and monkeys provided access to a treadmill and subsequently treated with MPTP. Findings indicate that exercise :

• reduces the behavioral impairments elicited by the dopaminergic neurotoxins

• PET imaging and biochemical or histochemical assessment = exercise-induced increase in the expression of neurotrophic factors, particularly

GDNF.

Exercise effects on motor and affective behavior and catecholamine neurochemistry in the MPTP-lesioned mouse.

• MPTP increased anxiety in the marble-burying test:

• sedentary lesioned mice buried more marbles

• exercise reduced anxiety on the elevated plus maze.

• Neither MPTP nor exercise altered symptoms of depression measured by sucrose preference or tail suspension.

• MPTP significantly reduced DA in striatum 5HT in amygdala and striatum

• exercise had no effect. Thus, exercise improves behavior in a model of DA depletion, without changes in DA or 5HT.

Endurance exercise training promotes angiogenesis in the brain of chronic/progressive mouse model ofParkinson's Disease.

• Abstract• GOALS AND OBJECTIVES: The main goal of this study is to

evaluate the effect of treadmill exercise on the angiogenesis markers in the striatum (ST) of chronic/progressive parkinsonian mice.

• RESULTS:• PD resulted in a significant decrease in blood vessel density with

the comparison between the sedentary control and PD model animals (p < 0.005). Four weeks of treadmill exercise training significantly increased angiogenesis in the striatum in ExPD groups (p < 0.05). Exercise also induced an increase in blood vessel density in the striatum of the control animals, but the change was not significant (P < 0.3).

• CONCLUSION:• These data suggest that 4 weeks of treadmill exercise promoted

angiogenesis in the brain of chronic Parkinsonian mice, which can partially explain the beneficial role exercise in patients with PD. Further studies are required to determine the mechanism of exercise-induced angiogenesis in PD.

• Nordic walking improves mobility in Parkinson’s disease

“We suspect that particularly PD patients benefit from Nordic walking because this is a much more ‘‘conscious’’ way of walking by facilitating rhythmic external cues.”

The influence of Nordic Walking training on sit-to-stand transfer in Parkinson patients. Gait Posture. 2011 Jun 1.

Exercise elevates dopamine D2 receptor in a mouse model of Parkinson's disease: in vivo imaging with [¹⁸F]fallypride.

• Abstract• The purpose of the current study was to examine

changes in dopamine D2 receptor (DA-D2R) expression within the basal ganglia of MPTP mice subjected to intensive treadmill exercise. Using Western immunoblotting analysis of synaptoneurosomes and in vivo positron emission tomography (PET) imaging employing the DA-D2R specific ligand [¹⁸F]fallypride, we found that high intensity treadmill exercise led to an increase in striatal DA-D2R expression that was most pronounced in MPTP compared to saline treated mice. Exercise-induced changes in the DA-D2R in the dopamine-depleted basal ganglia are consistent with the potential role of this receptor in modulating medium spiny neurons (MSNs) function and behavioral recovery. 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.

AAN: ‘Big’ Exercise Has Big Benefits in Parkinson’s

http://www.medpagetoday.com/MeetingCoverage/AAN/19593

• By John Gever, Senior Editor, MedPage TodayPublished: April 16, 2010Reviewed by Ari Green, MD; Assistant Professor, University of California, San Francisco andDorothy Caputo, MA, RN, BC-ADM, CDE, Nurse PlannerExplain to interested patients that TORONTO — Patients with Parkinson’s disease who participated regularly in exaggerated-movement exercises showed marked reductions in many symptoms, suggesting a degree of neuroprotection, researchers said here.

Shake Your Depression Office with Physical Therapy• By Vikki Alvarez, MDParkinson’s

Disease (PD) is a neurodegenerative condition that can disable the patient not only physically, but also emotionally. As the second most common neurodegenerative disorder that presents in Neurology clinic, it is not uncommon to see PD patients suffering from depression. Research shows that PD depression occurs in 40-50% of the patients. As a movement disorders doctor, my experience is that more than half of my PD patients either suffer from depression, admit to symptoms of depression, or ask me if they have depression.

Oral Medicine or

Supplements

Dopamine receptors

DA

L-DOPA

3-OMD

DA

Dopamineagonists

COMT inhibitors

Carbidopa

MAO-B inhibitors DOPAC

DA

3-MT

DA

DA

AADC

DACOMT

inhibitor*

L-DOPAL-DOPA

DADA

Blood-brain barrierPeriphery BrainNeuron

AAN: New Parkinson's Disease Treatment Guidelines

*Only tolcapone inhibits COMT in brain.

L-DOPA = levodopa3-OMD = 3-O-methyldopaDA = dopamine

AADC = aromatic acid decarboxylase DOPAC = dihydroxyphenylacetic acid3-MT = 3-methoxytyramine

ADAGIO Those people that delayed the use of Rasagiline started to deteriorate in their

symptoms prior to starting Rasagiline, especially in those with more severe symptoms.

25

Delayed Start (Placebo-Rasagiline)Early Start (Rasagiline-Rasagiline)

Olanow CW, et al. Mov Disord. 2008;23:2194-2201.

Week

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A

Superiority of slopes in placebo-controlled phase (weeks 12 – 36)

Are Curves Divergent?

C

Noninferiority of slopes in active phase(weeks 48 – 72; margin of 0.15)

Are Curves Nonconvergent?

B

Superiority of early vs delayed start at study end (mean UPDRS change from baseline to week 72)

Are Changes Different?

• Transgenic conversion of omega-6 into omega-3 fatty acids in a mouse model of Parkinson's disease, 2011 Canada

………higher cortical docosahexaenoic acid (DHA) concentrations were positively correlated with markers of nigral dopaminergic neurons such as the number of TH-positive cells, in addition to Nurr1 and DAT mRNA levels. These associations are consistent with the protective role of DHA in a mouse model of PD. Taken together, these data suggest that dietary intake of a preformed DHA supplement is effective in achieving neuroprotection in an animal model of PD.

Levodopa Induces Synthesis of Nerve Growth Factor and Growth Hormone in Patients With Parkinson Disease. Clin Neuropharmacol. 2011 Apr 29.

…….. Axonal degeneration may not be due to levodopa itself, as levodopa supports production of nerve growth factor and of

growth hormone.

• Lithium might have protective effect against Parkinson's disease, study finds

• Monday, June 27, 2011The drug lithium has been found to greatly prevent the buildup of the toxic proteins and brain cell loss linked to Parkinson's disease, according to a study conducted on laboratory mice.

• In previous animal studies, lithium, which is commonly used to treat bipolar disorder, has demonstrated a neuroprotective effect in diseases such as Huntington's disease, Alzheimer's and amyotrophic lateral sclerosis.

• Currently, investigators at the Buck Institute for Research have started preclinical studies to determine the proper lithium dosage for humans, and initiate Phase II clinical trials in conjunction with Parkinson's disease.

• Curcumin reduces alpha-synuclein induced cytotoxicity in Parkinson's Disease cell model

• Monday, May 02, 2011Results: ……Here we show that curcumin can alleviate alphaS-induced toxicity, reduce ROS levels and protect cells against apoptosis. We also show that both intracellular overexpression of alphaS and extracellular addition of oligomeric alphaS similarly increase ROS which induces apoptosis, suggesting that aggregated alphaS may induce similar toxic effects whether it is generated intra- or extracellulary.

• Conclusions: Since curcumin is a natural food pigment that can cross the blood brain barrier and has widespread medicinal uses, it has potential therapeutic value for treating PD and other neurodegenerative disorders.

“Neuroprotective Effect of a New DJ-1-Binding Compound Against Neurodegeneration in Parkinson's Disease and Stroke Model Rats.”

…………….. DJ-1 leads to a prevention of

oxidative stress and cell death in the substantia nigra, leading researchers to conclude that comp-23 has a neuroprotective effect and should become a fundamental drug for PD therapies.

……….. team found that phenylbutyrate could activate DJ-1 and keep dopamine neurons from dying.

Sodium Benzoate, a Metabolite of Cinnamon and a Food Additive, Upregulates Neuroprotective Parkinson Disease Protein DJ-1 in Astrocytes and Neurons.

J Neuroimmune Pharmacol. 2011 Jun 24. • Discovered anti-inflammatory activity of

sodium benzoate (NaB), a metabolite of cinnamon and a widely-used food additive. Here we delineate that NaB is also capable of increasing the level of DJ-1 in primary mouse and human astrocytes and human neurons highlighting another novel neuroprotective effect of this compound.

High serum vitamin D decades before onset is associated with lower risk of Parkinson’s disease, according to a new study. Serum samples taken in the late 1970s from 3173 individuals taking part in the Mini-Finland Health Survey were tested for vitamin D levels. ……

“Our findings are thus consistent with the hypothesis that chronic inadequacy of vitamin D is a risk factor for Parkinson disease,” the authors conclude. “The exact mechanisms by which vitamin D may protect against Parkinson disease are not fully understood…Because of the small number of cases and the possibility of residual confounding, large cohort studies are needed.” Arch Neurol 2010;67:808-811

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