In April 2022, the Parkinson Foundation hosted a webinar with movement disorder specialist Dr. Joash Lazarus on possible treatments for slowing the progression of Parkinson’s disease (PD).  In this webinar, Dr. Lazarus discussed the neuroprotective possibilities of treatments such as rasagiline, levodopa, deep brain stimulation, and the impact of exercise on PD progression.  He said that the best treatment for PD that puts the brakes on progression and is neuroprotective is exercise.  

In neurodegenerative disorders, there is a hope of finding a therapy that causes neuroprotection, and slows down the disease progression in the brain.  To date, none of the pharmacotherapies and medications has overwhelming evidence that it slows down the process in the brain.  A study done on the drug rasagiline showed that the medication could alter the disease process, but there wasn’t overwhelming evidence that it was neuroprotective.  Despite this, rasagiline is still seen as an effective treatment tool for PD, and is often used in combination with levodopa.  

Similarly, a levodopa study done in 2004 showed that levodopa does not have a disease modifying or neuroprotective effect, but is still the gold standard for medication management because of its symptomatic benefit. 

Deep brain stimulation (DBS) studies have shown that patients who had DBS had a lesser degree of worsening symptoms over time than patients who only had medication management.  Additionally, after five years, many people who did have DBS only needed one kind of medication, and those who did not have DBS needed two to four categories of medication.

Exercise is the best treatment for PD that puts the brakes on progression and is neuroprotective.  Exercise can help with motor and cognitive behaviors, and can reduce falls.  Additionally, aerobic exercise improves brain functions such as attention, executive function, memory, and balance.  Vigorous exercise appears to be neuroprotective, as people with PD who reported regular exercise had less cognitive decline after 1 year.  

When exercising, the amount of time and intensity matters.  Dr. Lazarus recommends 150 minutes per week with an elevated heart rate and enough activity to be sweating and feel fatigued but not exhausted or in pain.  See your physical therapist or doctor for an exercise prescription. 

For more information on the benefits of exercise, see this Stanford Parkinson’s Community Outreach page: 

Benefits of Exercise for PD

For a list of PD exercise videos, see this Stanford Parkinson’s Community Outreach page:

PD Exercise Videos

For more information on PD medications, see this Stanford Parkinson’s Community Outreach page:

PD Medications

For more information on Deep brain stimulation (DBS), see this Stanford Parkinson’s Community Outreach page

The webinar recording can be viewed here

Please see below for notes on the April webinar.

Regards, 

Joëlle Kuehn

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“Can we put the brakes on PD progression” 

Speaker:  Joash Lazarus, MD, movement disorder specialist, Multiple Sclerosis Center of Atlanta

Webinar Host:  Parkinson Foundation

Webinar Date:  April 6, 2022

Summary by:  Joëlle Kuehn, Stanford Parkinson’s Community Outreach

Current therapeutic approaches in PD

• Diagnosis, patient and community education
• Pharmacotherapy:  Main goal is to improve motor symptoms with the goal of improving function, preventing disability, improving quality of life
• Join support groups:  Social support; Mental health support
• Participation in clinical trials:  Geared to addressing biochemical disorders
• Other therapies:
  • Gait and balance problems: PT and exercise 
  • Speech, massage, mindfulness-based therapies
• Continuous dopaminergic stimulation
• Deep brain stimulation (DBS):  Become more common because of its efficacy

Neuroprotectivity

• Looking at to which degree protein accumulates and which dopamine is depleted
• The hope for neurodegenerative disorders is for neuroprotection so if we can develop a therapy that is effective enough in slowing down the process in the brain
• To date, none of the pharmacotherapies and medications have overwhelming weight of evidence that it slows down the process in the brain
• Normally PD is treated through symptom control, with the goal to be reducing symptoms and increasing quality of life
• PD treatment has the goal of neuroprotection and slowing down disease progression
• Question is if medications are slowing down the process in the brain, or covering up the symptoms, which is still useful and important

ADAGIO study

• Studied efficacy of rasagiline/Azilect in symptom control 
• 2 groups of patients:
  • Group 1: early start group:  Started rasagiline at beginning of the study, were followed for 72 weeks.  Had neurological examinations (UPDRS)
  • Group 2: delayed start: group:  Second group was on a placebo (inactive) substance for 36 weeks before being switched to rasagiline
• Compared the two groups UPDRS scores over time
• If a medication was truly effective in slowing down the disease process, then the trajectory would be similar between the two groups when they were both on the active medication, but the group that started later would never quite catch up to the first group
• Group 2 never reach the same degree of disability control because they started later, meaning the sooner you start, the better it is, and it is likely because it is impacting the disease process as a whole
• Placebo got worse for the first 36 weeks because they were untreated, but did much better after 48 weeks
• At 72 weeks, the delayed start group never caught up to the group that started earlier, although had improvement
• Suggested the possibility that rasagiline could alter the process involved in PD, but not overwhelming evidence that it was neuroprotective due to dosing at different levels having inconsistent results
• Rasagiline is still seen as an effective treatment tool for PD.  Often used in combination with levodopa

Levodopa study:

• There was a delayed start study, similar to the rasagiline study but for levodopa in 2004

• For levodopa, patients in the delayed start group caught up very quickly to those in the early start group for levodopa
• Suggesting there wasn’t a real benefit in this study design for patients, as they both ended with the same symptomatic benefit
• Levodopa does not have the disease modifying and neuroprotective effects we aim for but is still the goal standard for medication management because of the symptomatic benefit it converts

Deep brain stimulation (DBS) studies

• Transformed way we control motor features in PD
• To qualify for DBS, a PD patient must have 4 to 4.5 years of symptom onset with 6 months of motor complications (i.e. dyskinesias, tremors)
• Patients who had DBS had a lesser degree of worsening symptoms over time than patients who only had medical management
• DBS is significantly effective for tremors 
• After 5 years, many people who did have DBS only needed one kind of medication, and those who did not have DBS needed two to four categories of medicine in comparison (polypharmacy)

Role of diet and nutritional supplements in PD progression

• Looked at fresh fruits (½ cup), fresh vegetables (½ cup), nuts (¼ cup or 2 tbsp spread), fish (4 oz), olive oil (1 tsp), and wine (6 oz)
• Components are part of the Mediterranean diet
• Eating more of these showed a positive impact in patients self-reported function at 6 and 12 week mark

Exercise

• Can help with motor and cognitive behaviors
• Exercise improves synapses and brain health, which improves circuitry, which changes behaviors 
• Exercise has pleiotropic benefits that extend to more than just one circuit in the brain, and benefits extend to not just PD but overall body and brain health
• Exercise has diverse benefits and an improved brain health as a whole

Potential neuroprotective mechanisms of exercise in PD

• Protection of dopaminergic neuron loss (2010 study):  Animal model showing that 3 months of exercise completely protected against MPTP induced damage
• 2004 study showed a restoration of dopaminergic and glutamatergic balance in the striatum
• Upregulation of neurotrophic factors.  Ex. BDNF
• Attenuates mitochondrial dysfunction and oxidates stress

Benefits of exercise in the elderly:  fall reduction

• Falls are common in the elderly
• PD patients fall frequency is 3x higher than the general population.  There is a 46-68% chance of falling more than 1x a year
• Up to 50% of falls result in injury
• Fall related injuries are the top causes of morbidity, loss of independence, and increased health care costs
• Preventing falls in the elderly and in neurologic disorders is a high priority in most healthcare systems in the UK, US, and Europe
• Exercising reduces PD disability (on the PD H&Y Stage III)

General benefits of exercise

• Prevention of cardiovascular complications

• Slows down osteoporosis
• Improved cognitive function
• Prevention of depression
• Improved sleep
• Decreased constipation
• Decreased fatigue
• Improved functional motor performance
• Improved drug efficacy
• Optimization of dopaminergic transmission 

Exercise improves brain function

• Exercise improves heart and lung function which improves motor function, attention, and cognitive speed
• In general, aerobic exercise improves:
  • Attention, executive function, and memory in healthy older adults
  • Memory, executive function, and balance, in people with Alzheimer’s disease
  • Working memory, processing speed, and visual learning in people with depression

Multi-tasking in PD

• With frontal cognitive dysfunction and mild cognitive impairment, speed and quality of gait are negatively affected by a dual-task activity
• Dual-tasking is a good test technique to separate out and test gait and balance dysfunction
• Additionally, with PD you have an impaired “autopilot”, so now you have to think about all movements and proper posture that used to come naturally and without thinking
• Therefore, performing more than one task at a time may lead to falls

Exercise improves brain function in many ways

• Increases BDNF levels in healthy adults and in people with PD
• In PD:
  • Moderate-intensity aerobic exercise, 45-60 minutes 3 times per week
    • Improved executive function
  • Progressive resistance exercise, 60-90 minutes 2 times per week
    • Improved working memory, executive function, and attention
  • Large, randomized controlled trial of high-intensity treadmill exercise (4 days per week, either 60-65% or 80-85% maximum heart rate):
    • Improved mobility compared with moderate-intensity workout and usual care
• Vigorous exercise appears to be neuroprotective
  • People with PD who reported regular exercise had less cognitive decline after 1 year
  • Still requires long-term/prospective research to confirm this

SPARX study

• Looked at change in UPDRS motor score over 6 months across groups with different exercise regimens
• 3 groups of people:
  • 80-85% elevated maximum heart rate
  • 60-65% elevated maximum heart rate
  • Usual care
• Those with the highest intensity of exercise have no change in score, and those with medium had a slight increase in the score, with those who had usual care having an increase in the score.  The higher the score, the worse the motor function

Exercise registry study

• Self reported study to see what exercise habits of those with PD were
• 4886 individuals with PD
• 44% did more than 150 minutes of exercise per week
• 20% did “low exercise” (less than 150 minutes per week)
• 36% did no exercise

Important findings

• Regular exercise = better quality of life, physical function, less depression
• 1 year later, physical activity at baseline = better quality of life, mobility, physical and cognitive function
• The amount of time and intensity matters

Best exercise “prescription” for PD

• 150 minutes per week
• Heart rate elevated
• Sweating
• Enough to feel fatigued but not exhausted or in pain 

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Question and Answer:

Question:  What is the difference between neuroprotection and neurorestoration?

Answer:  There is a lot of overlap.  The goal of neuroprotection is to slow down the brain degeneration and loss of dopamine.  Neurorestoration is to try to restore and get back to the baseline the function that was lost.  For example, exercise may slow down the process in the brain but it will not bring the patient back to how they were before the diagnosis. DBS has some of the neurorestorative features because it can improve tremors and function. 

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Question:  How do you advise your patients to consider DBS?

Answer:  My approach is to highlight the positive impact of DBS.  In the clinic, we focus on interventions and timing that is well-established.  This means several years or even decades of research that has been replicated so we know it is safe and effective, which DBS is.  The best approach to take is suggested first after a minimum of 4-5 years after symptom onset, and for symptoms that are not adequately controlled with medications.  DBS does what levodopa does, but without complications such as dyskinesias.

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Question:  Does DBS help with parkinsonian symptoms like stiffness, freezing of gait, or rigidity?  Does it help or hurt cognition?

Answer:  It’s easier to separate it into motor and non-motor symptoms.  For motor symptoms, DBS is absolutely effective for tremors and dyskinesias, and improves to the point where patient function is much better, they are happier and they are doing much better from a disability standpoint.  

Freezing is a little more complicated, but if those episodes of freezing get better with levodopa dosing, there is a good likelihood they would also get better with the DBS surgery.  A small group of patients can have freezing even when they are on dopamine, and those episodes probably won’t get better with DBS, but this depends on the frequency of the freezing events and how bad they are freezing.

For non-motor symptoms, we don’t try to address the nonmotor symptoms with DBS as a whole.  From a cognitive standpoint, DBS is very safe, especially for those that still have a well-preserved cognition.  It will not worsen depression.

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Question:  What is more effective for slowing PD progression, medications or exercise?

Answer:  Many patients will only see the benefits of exercise if they reach the high intensity level which is 60-65% of your heart rate, which is where you will really be sweating.  For a person with tremors or freezing, it’s only possible to exercise at that level when you have a good dose of medication.  The combination proves best and is individually determined.

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Question:  Is there a dose response?  How much exercise is enough to be helpful?

Answer:  There is a dose response for heart rate and exercise duration, but the target heart rate changes per person.  80-85% intensity is the goal where we start to see improvements.

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Question:  Does DBS make exercise more difficult?

Answer:  It shouldn’t, it should help.

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Question:  Does exercise help you take less medication?

Answer:  Absolutely, studies have shown those who exercise have fewer medication increases.