Expert Briefing: Can We Put the Brakes on Parkinson's Disease Progression?

Dr. James Beck 00:00:01
My name is Dr. James Beck. I'm the chief scientific officer at the Parkinson's Foundation, and it's my pleasure to welcome you to another session of our Expert Briefings. Today's topic is "Can We Put the Brakes on Parkinson's Disease Progression?"

I'm just going to go over a little bit to familiarize you with our Zoom interface. I know we have many people who know this quite well, but we always have new people each time, and I just want to make certain everyone's comfortable. At the bottom of the screen, you'll see a red arrow that highlights our chat. This is where my colleagues will share information, so this isn't where you would ask questions. We'll get to that in just a second.

My colleague Danielle will be sharing information about resources that the Foundation provides, a place to download slides, information on calling, and other details you may need to know. On the next slide, we show you the button for the Q&A. That is where you will actually click and ask your questions. If you're on Facebook, don't worry, you won't be able to click on the button, but you can send questions to the Foundation via the comment section.

This is a way that my colleagues will be looking for questions that come in so I can ask them of our speaker today. The last thing to point out to you is the live transcript. This is a relatively new Zoom feature that will provide a closed-captioning-like experience. If you're having a little trouble hearing, or you're in a noisy environment, you can see closed captioning at the top of your screen. It is computer-generated, so it's not going to be perfect, but it should give you a good sense of what is being discussed.

On the next slide, I just want to talk a little bit about the mission of the Parkinson's Foundation. The Parkinson's Foundation is a nonprofit that's focused on improving the lives of those living with Parkinson's, both through improving care and advancing research. I think it's important that everything we do is done in close contact with our community to ensure that our actions are aligned with the needs and priorities of those living with Parkinson's.

On the next slide, we outline our goals here. It's important to note that we are focused on improving care for those living with Parkinson's disease, advancing research toward a cure, and empowering our global community. I think our Expert Briefings series is but one way we do that. We certainly rely on the Parkinson's community to inform our structure and our agenda for the year for the Expert Briefings. But our Expert Briefings really wouldn't be possible without the support of our sponsors, so I want to take a moment to give them thanks.

Dr. James Beck 00:02:27
Our Expert Briefing series for this year is supported by a grant from Genentech, which is a member of the Roche Group. We're supported by the Light of Day Foundation, whose generosity has made our PD Health @ Home programming possible as well, and by support from Kyowa Kirin. Thanks to all three sponsors for our Expert Briefing series this year.

I just wanted to mention that our Expert Briefings are recorded and archived. Within a week, you should get an email, if you've registered for the Expert Briefing, that it's available for download. That's something to look forward to. In case you're not able to take notes, or you want to share this with others, it's available online. We also make the slides available for download. If you want to have those separately, you can. There's a link in the chat. Click there, and you can download a PDF version of that.

What I'd like to do next is get to know who our audience is. I always like to do that. If you're viewing on Facebook Live, just use your comment section to let our colleagues know who's listening. We're just trying to get a sense of what our audience is like. We have a lot of people with Parkinson's, as I suspect. Sometimes we have a good selection of nurses, scientists, clinicians and people who are really interested in Parkinson's disease. Let that go for just a brief moment, and hopefully we'll see what our breakdown is in just a second.

Not surprisingly, we have a lot of people with Parkinson's who are listening, and we welcome them, as well as their care partners and a good number of people who have family members with Parkinson's disease. Welcome to everybody.

Next, I'd like to introduce our presenter, Dr. Joash Lazarus. Dr. Joash Lazarus is a graduate from the University of the Witwatersrand Medical School in Johannesburg, South Africa. I hope I pronounced that correctly. Following a primary care internship in his home country, he joined the movement disorders section at Emory University to pursue research training in neurology and genetics.

Dr. Lazarus completed neurology residency training, as well as a clinical fellowship in movement disorders. He is board-certified by the American Board of Psychiatry and Neurology and has that specialty focusing on movement disorders. His clinical and research interests revolve around the evaluation and management of balance disorders, such as those seen in multiple sclerosis, Parkinson's disease and other movement disorders. It's my distinct pleasure to welcome Dr. Lazarus to our presentation, and now I'll turn it over to you. Thank you.

Dr. Joash Lazarus 00:05:34
Thank you, Jim. Thank you for the invitation to present today, everyone.

As Jim mentioned, the title of today's talk is "Can We Put the Brakes on Parkinson's Disease Progression?" Just as a summary leading into this, Parkinson's, of course, is caused by an aggregation or accumulation of essentially a toxic protein called alpha-synuclein in very strategic areas of the brain that results in a depletion of dopamine. Dopamine is that messenger that's very important in controlling, among other things, smooth and coordinated movement. The consequences of that are all the symptoms we typically see in Parkinson's.

But we have to be mindful that everyone's experience with the disease itself is very different. There are no two similar disease experiences, and with that in mind, there are no two identical treatment approaches that are typically used. As a general paradigm, this is often the algorithm or the set of tools that we use when approaching either a newly diagnosed patient or when confirming a patient with a diagnosis of Parkinson's disease. That current therapeutic approach draws on one or more of these modalities at any given time during the entire experience.

It's often a new diagnosis, followed by some form of either in-clinic and continuing patient and community education. We're very quick right now to emphasize early pharmacotherapy. The pharmacotherapy, or the drug therapy, is really aimed at controlling motor symptoms, and to a lesser extent the non-motor symptoms, with the goal of improving function, preventing disability and improving overall quality of life. Those three things — improving function, preventing disability, improving quality of life — really remain the cornerstone of managing Parkinson's disease. That's the goal in treating the symptoms related to this disorder.

There are different modalities and different ways in which we can approach that. Pharmacotherapy is listed very high on this list as one option. The others are support groups, social support, mental health support — mental health in terms of prevention of mental health complications — and participation in clinical trials. All of those are really geared toward addressing the underlying biochemical disorders.

Other forms of therapy are very useful and have proven benefit in this disorder. For gait and balance problems, for example, we have very specific evidence-based treatment options now. Things like BIG therapy and LSVT therapy, for example, have shown that they can really improve not just symptom control, but with it, the quality of life and function that patients can have.

Dr. Joash Lazarus 00:08:19
Massage therapy, mindfulness-based therapy — there is a plethora of complementary therapies that really help the clinician form a more comprehensive approach to managing these symptoms. We also have the benefit of more advanced pharmacotherapies now. Continuous dopaminergic stimulation, for example, a Duopa pump, and then DBS surgery, which has become more common because of its efficacy, which I will underline a little later.

If you look at all these therapies as a whole and across the spectrum, often we are looking at it through different perspectives and we're asking different questions. In the scientific fraternity, so to speak, we're looking at the disease and the disease process. In other words, the degree to which that protein accumulates and the degree to which dopamine is depleted. The holy grail of any neurodegenerative disorder is the concept of neuroprotection. Can we discover or develop a therapy that's effective enough in actually slowing down that process in the brain?

To date, and I will go through several examples that highlight this, none of the pharmacotherapies, none of the medications or none of the complementary therapies like DBS surgery have overwhelming weight of evidence to support that it actually does that. It actually slows down the process in the brain.

But that's okay, because really what's more pertinent on a day-to-day basis for patients, and in terms of our interaction as clinicians in a clinic visit, is: how are you doing functionally on a day-to-day basis, and how are you progressing, if at all? The types of things that we're really interested in, and patients find most relevant, are from a functional standpoint: are they able to cope or manage as efficiently or effectively as they did three months ago or six months ago? Is there any degree of disability or discomfort that's disrupting their life now compared with previously, and how do we manage that?

Symptom control, kind of masking the symptoms and the process that's there, is a little bit different from controlling disease progression or neuroprotection. Often, in the clinic, it may seem like we use those interchangeably, but they're a little bit different. This goal of neuroprotection, of slowing down this disease process, has been the focus of research for many, many decades. The question is: how do we determine or answer whether any intervention, whether it's a medication or a lifestyle change, is actually effective in slowing down this process in the brain, or if it's merely covering up the symptoms, which is still very potent, still very useful and not trivial at all?

Dr. Joash Lazarus 00:10:50
This is a good example of how we would design a study to do that. This study was called the ADAGIO study. It was published in 2009, and essentially it was to look at the efficacy of rasagiline, or Azilect, in symptom control, number one, but also whether or not it actually impacted that disease process. To answer that question, there were two groups of patients in the study. Apologies for that.

There was an early-start group. This was the group of patients in this lower bar here, who started the active ingredient, the rasagiline, very early on at the start of the study, and they were followed for 72 weeks. During that process, they had neurological examinations. The examination we use is called the UPDRS. It's a way of us quantifying all the motor deficits that we see on exam that's relevant to Parkinson's. Of course, a higher score is relevant to less controlled symptoms as a whole.

Then there was a second group of patients who started on a placebo, so an inactive substance, until 36 weeks before they were switched to rasagiline.

To summarize, there were a few important endpoints here, but if a medication were truly effective in slowing down the disease process, then the trajectory would be very similar between the two groups when they were both on the active medication. In other words, they would both respond to Azilect, as they did here. But the group that started later, which is the placebo group, would never quite catch up to the first group. It would never quite reach the same degree of disability control because they started later, which means the sooner you start, the better it is, and that's likely because it's impacting the disease process as a whole.

If you look at the trajectory of this graph, you see that the placebo group steadily got worse, as you'd expect, because they were untreated for the first 36 weeks. When it was then switched to rasagiline, they did much better out to 48 weeks, and it was similar or parallel to the group that was on rasagiline. At 72 weeks, you notice that the delayed-start group, the group that started later, never caught up to the group that was on the active medicine from the beginning. They didn't do quite as well, although they had some improvement from the time they started the active medication.

Dr. Joash Lazarus 00:13:07
Those were optimistic features that suggested the possibility that Azilect, or rasagiline, could perhaps alter the progress of the process that's involved in Parkinson's, with the caveat that two doses were studied. There was a 2-milligram dose and a 1-milligram dose. Although the 1-milligram dose met the criteria, or the features that we look for in a so-called neuroprotective or disease-modifying agent, the 2-milligram dose did not.

It remained uncertain. There was not overwhelming evidence, unfortunately, that rasagiline was neuroprotective or could protect the brain from the processes that were underlying the development of Parkinson's disease. There is still ample evidence from this that patients who are on rasagiline do better. Their symptoms are better controlled, and it's still a very effective symptomatic treatment, which is why it's used as an adjunct to the gold standard levodopa even today.

Speaking about levodopa, or Sinemet, this was the equivalent study — a delayed-start study using the same kind of methodology in 2019 — to try to answer that question related to levodopa. The background to levodopa, which is Sinemet by brand name, or by generic name comes in different formulations, is that the science behind it was well established in the 1960s. It's been a mainstay in terms of oral treatment for Parkinson's disease ever since then.

In early 2004, there was a study that showed that potentially levodopa therapy either had a prolonged symptom effect or could potentially attenuate the disease process, or be neuroprotective. The way that study was done is that patients were either on placebo or levodopa for four weeks and then taken off medicine for two weeks. Even two weeks later, patients who were in the levodopa-treated group still did a lot better than those who were in the placebo group.

But the study design was very similar to the one that I'm about to show you, because this really is the best way of elucidating whether a medication or any intervention is covering up the symptoms and is symptomatic, or is slowing down the process.

Dr. Joash Lazarus 00:15:09
In this study design, if you look at the first graph, the delayed-start group here compared to the early-start group, once the delayed-start group began an active medication at around 40 weeks from randomization, they caught up very quickly to those who started earlier on. That suggested that there wasn't a real benefit in this study design for patients who delayed starting Sinemet or levodopa until later on. They both had the same symptomatic benefit.

The same was true if you look not just at the motor features like tremor, dyskinesia or stiffness, but if you look at the quality of life that was self-reported using the scale we call the PDQ-39 total score. This was a great study that was done three years ago that showed that levodopa, unfortunately, probably does not have the disease-modifying and neuroprotective effects that we aim for, but it's still very much the gold standard in terms of medication management because of the symptomatic benefit it confers.

Deep brain stimulation, of course, is a great adjunct therapy. It's more than just an adjunct therapy. It has really transformed the way we control motor features in Parkinson's disease. The FDA approval of the label for DBS in Parkinson's patients is roughly around four and a half years — four to four and a half years — of symptom onset, with about six months of motor complications.

Those complications are things like uncontrollable involuntary movements, such as dyskinesia; wearing off, when the medication kind of loses its effect sooner and sooner; or just tremor that never gets better, even on an optimal dose of levodopa medication. Several studies have shown a profound benefit for DBS and shown that it's very safe in the correct clinical setting, and that the long-term outcomes are also very relevant and well-established.

One of the questions that needed to be answered was whether starting patients on DBS, or proceeding with DBS early on, would alter the long-term outcomes and perhaps hint at the possibility of some neuroprotective effect.

This study, which was published two years ago from the Vanderbilt group, looked at patients between six months after diagnosis or six months after symptom onset to four years, so really early on in the disease process. Here they were randomized to two groups. They were randomized to early DBS, which is the black line, in addition to medical management. If patients were on Sinemet plus Azilect, they remained on the medications, of course, versus those who were randomized to only aggressive and the best possible oral medications that they could be on.

Looking across the five-year follow-up period, you notice that those patients who were randomized to the DBS group had an improvement in their overall motor scores, or had a lesser degree of worsening over the five years than patients did with just medical management. If you look at tremor specifically, the impact of DBS on tremor is really very effective, and that's been shown in several blinded randomized controlled studies in the past.

Even in this study, which is consistent with that, you notice that the tremor continues to improve and shows long-term efficacy, a long-term response to DBS, out to five years.

Dr. Joash Lazarus 00:18:13
Patients with oral optimized drug therapy followed the natural history of that. The expectation, in other words, is that symptoms generally progress a little, and in this group there was worsening of tremor in the five years after study enrollment and improvement of tremor in the five years after study enrollment in the DBS group.

Another way of looking at the efficacy is patients' total levodopa daily dose. Again, patients who had DBS early on had a lower increase in the total amount of dopamine they were taking out at five years, whereas patients who did not have DBS were likely to have a much higher increase, a much higher total daily dose of levodopa five years later in comparison. The same is true of using other medications.

The red bar here represents patients who did not have DBS early on and only had optimized drug therapy. A higher percentage of them needed two, three or four categories of medicines — so polypharmacy — in comparison to those who had DBS, in which they were much more likely to remain either on one medication treatment option or fewer medication options. The one graphic I did not include here was dyskinesia, but dyskinesia follows a very similar trend to that of levodopa dose and tremor, in that, in general, patients who had early DBS, as well as optimized drug therapy, generally did better with dyskinesia control.

Now moving away from that, we spoke about two of the pivotal neuroprotective trials, which were unfortunately unsuccessful but still very positive in terms of symptomatic benefit. We spoke about surgical management. Other areas of focus are the holistic approach to managing Parkinson's symptoms, and that includes evaluating lifestyle strategies, including nutrition and exercise, which we're going to focus on a bit.

This is a study from 2017 from Dr. Laurie Mischley, and it's a self-report scale. Patients completed this scale at different intervals during the study and at baseline, noting the quantities of how much of each of these food types they consumed during the 12-week study and beyond. There was an extension phase as well, correlating that to quality of life and functional symptoms measured by something called a PRO-PD score.

This PRO-PD score looks at different complexes of symptoms. It looks at overall motor function, like tremor, fine motor dexterity and balance. It looks at cognitive scores from a subjective standpoint — so how patients and their caregivers feel like they're doing — including energy, and then non-motor symptoms as well.

Dr. Joash Lazarus 00:20:45
You notice that I'm including really the positive symptoms here. A lot of these components that fall under the Mediterranean diet had a significant p-value, so had a positive impact in patients' function as self-reported at the 12-week and six-week mark. It's growing evidence, which had been established previously, of the benefits of the constituents of a Mediterranean diet in symptom control.

Again, the manner in which the study was done may not have been robust enough to look specifically at neuroprotection or disease progression in the way we think of it from a preclinical scientific basis. But in terms of patient-reported outcomes, patients basically felt better and did better at a time point of 12 weeks, which is very reassuring and something we can definitely use on a clinical basis.

We spoke about medications to begin with, and we tried to broaden our approach into how we look at therapeutic modalities in Parkinson's disease. By beginning with that, we really focused on a couple of things. The medications are very often very specific, but they're very effective in dealing with the neurotransmitter and the biochemical dysregulation that occurs in Parkinson's. DBS is really very exquisitely effective in terms of targeting circuitry that's involved in both symptoms and side effects.

In doing so, both of those can help to modulate behaviors, and motor behaviors being the predominant target here — things like tremor, mobility and overall global motor function. But this is a bidirectional circuitry, a bidirectional relationship. Patients' adaptive motor behavior can also have an impact on the circuitry, on general brain health and possibly on the neurotransmitters and different synapses as well.

When we look at other lifestyle changes, one that has recurred across the literature for neurodegenerative disease has been exercise.

Of course, trying to summarize a plethora of research findings here, a take-home point from much of that literature is that exercise has what we call pleiotropic benefits. It has benefits that extend to more than just one circuit in the brain that may be relevant for Parkinson's, and more than just a couple of neurotransmitters. It really has diverse benefits that we'll go into on a clinical basis, and diverse benefits on brain health as a whole, as well as a behavioral health perspective.

But let's stop before we get to the clinic and before we get to patients. What about any evidence or any proof that this actually works in Parkinson's disease? Here's a summary, and this is a very brief synopsis of a wealth of evidence that's been done in the lab looking at different lab models of Parkinson's disease. There are rodent models, and there are primate models as well.

Dr. Joash Lazarus 00:23:15
For example, there have been studies by Gerecke et al. that showed that, in a specific animal model, those that were forced to do high-intensity exercise, when you induce Parkinson's in these animals using a toxin called MPTP, the amount of damage that was incurred in those animals was less than in the lab rats that were not forced to exercise, basically. Exercise could modulate the amount of MPTP-induced damage. We know that this concept right here, neurotoxin-induced damage, is often used as a disease model, as a surrogate to try to understand the disease process in humans as well.

In a similar type of experimental design, it was shown that dopaminergic balance and glutamatergic balance in the striatum were restored somewhat. What that basically means is that we know in Parkinson's you lose some dopamine; that's one of the messengers for movement. In some of the circuits that overlay Parkinson's, there's an excess of another messenger called glutamate. That balance is disrupted.

Glutamate excessively can cause some of the tremor or lead to some of the downstream consequences that result in things like tremor and dyskinesia. Restoring the balance between the two may, down the line, help to open up avenues in which we can understand and maybe manage those symptoms a little bit better.

A more consistent finding across both animal and clinical data is that certain neurotrophic factors, certain proteins and certain molecules in the brain after exercise are upregulated. They're expressed to a higher degree, so you have higher levels of them. One of those is called BDNF, which I will speak about later. All of these are really on the molecular level, even within individual cells as well.

Mitochondrial dysfunction and oxidative stress are things where, with time and exposure to different stresses, the power plant, the energy supply to the neurons of the brain, becomes dysfunctional. Exercise has a means of trying to reduce that damage within models that try to replicate the Parkinson's disease process.

The benefits of exercise are seen across the age spectrum, of course, but also in elderly patients. Here's some of the reasons why. One of the biggest unmet needs in the clinical practice of Parkinson's is, of course, falls and trying to prevent falls. They're very common not just in the PD population or in the geriatric population as a whole, but in PD patients, the fall frequency is about three times that of the general population on an annual basis, and half of them can result in a major injury. Of course, the number of falls doesn't really matter on a personal level if you have one severe fall. Preventing that is really at the top of the list of the healthcare demands in terms of movement disorders.

If you quantify the cost to the healthcare system in fall-related injuries, they're one of the leading causes of morbidity and downstream consequences, like the loss of independence and the increased healthcare costs that emanate from them. Preventing falls in the elderly, and especially in this subpopulation with neurological disorders, has naturally become a priority in a lot of healthcare systems. Exercise is one possible solution to that.

Dr. Joash Lazarus 00:26:11
It does that through a number of different targets. It's really well known how exercise has good benefits for the heart, so in preventing cardiovascular complications. We also now know that it can slow down osteoporosis. In general, it can improve cognitive function and prevent things like depression and anxiety, things that have become even more prevalent with the pandemic. Those can have rebound effects on sleep and energy as a whole.

If you look at the last three or four bullet points here, these are all non-motor symptoms that are even better represented, even more common in the Parkinson's disease population, and so could be of relevance here in terms of how we manage them. Things like constipation and fatigue, we know that they are not uncommon among PD patients. Overall functional motor performance — that's the hallmark of the disease process that we're trying to manage.

Specifically, what has been done in Parkinson's? How do we know the relevance of the overlap between the two? There is this suspicion that those populations that have a higher exposure to exercise have improved drug efficacy. Also, optimization of dopaminergic transmission, meaning that dopamine that's there, with or without improving the levels of dopamine, the efficacy with which it's used could be better, and some suspicion of neuroprotection, which we had spoken about briefly previously, that I'll go into in the next couple of slides.

What about those pleiotropic effects that I mentioned before? Exercise improves brain function in many ways. We know that it improves cardiac function and, of course, lung function, and in doing so, it can really have a positive impact on overall motor function, attention and cognitive processing speed. We know that aerobic exercise specifically has very well-described benefits and characteristics in neurocognitive profiling.

Patients who are involved in aerobic exercise on a frequent basis, compared to those who are involved in other forms of exercise, really show benefit in terms of attention and executive function — things like multitasking, for example — as well as memory. Even in those with a specific disease process, not necessarily Parkinson's, but this study looked at Alzheimer's, those aspects were improved: memory and executive function. Those are hallmark dysfunctional areas in patients with Alzheimer's. As expected, with it, so did their balance.

Dr. Joash Lazarus 00:28:40
If you look at non-neurologic patients, so patients who don't necessarily have the title of the process of a neurologic disease, patients with depression also show benefit from this, in that their working memory, processing speed and a certain type of learning or memory called visual learning were improved. Even though these are different patient populations, they share a lot of characteristics and challenges that characterize the Parkinson's disease process. It is very interesting to look at whether this could help the PD population in general.

If you look at cognitive functioning, one of the hallmark features of cognitive dysfunction in PD is a frontal cognitive dysfunction and something we call mild cognitive impairment. Essentially, things like multitasking and processing speed are affected. We know that, in terms of cognitive dysfunction, it correlates, it tends to go hand in hand, with some of the gait dysfunctions and balance impairments that happen in patients with PD.

If you had to characterize from a lab basis how patients with Parkinson's mobility and walking change, a consistent theme is that their speed and the quality of gait are negatively impacted early, but also negatively impacted even more by a dual-task activity. What that means is that if you had to give a patient a cognitive task — count backward, tell me the months of the year — and a gait task at the same time, that it becomes almost overbearing at times, and you can unmask deficiencies, you can unmask problems in a gait pattern.

Dual tasking is a good lab-based technique to separate out gait and balance dysfunction, but it's also a very good target in terms of rehab programs to try to address some of the dissonance that we see in Parkinson's disease. A better way to think of that is that in PD, because the multitasking and executive function aspects can be very prominently affected early on, things like walking, which were previously on autopilot, now become very conscious, and you really have to think about your movements. You have to be purposeful about them in order to prevent falls or in order to be effective in doing so.

Even more concerning, often, is that performing more than one task at a time can lead to falls. Often, this is impossible to ignore.

Downstream, the longer-term effects of exercise on Parkinson's are well established in terms of the degree of disability. The two pyramids are very similar in content here, but the size of them differs. If you compare the pyramid on the left, for example, it's a group of patients — a simulated group of patients — without exercise. Those on the right, you notice that the second or the top portion of the pyramid is smaller in the group on exercise. That's meant to communicate that all the secondary disability that's derived from Parkinson's is often attenuated with exercise in comparison to a group of patients who do not have that.

What do I mean by primary and secondary disability? We think about the disability that emanates from direct symptoms of Parkinson's as being a primary one. So the slowness or the stiffness, more commonly the tremor, dyskinesia and postural instability, cause a lot of disability in patients. But even in mild primary dysfunction, long-term consequences of that include things like deconditioning, a loss of muscle strength and muscle bulk, some proximal weakness and contractures. Those are all complications of long-term primary symptoms of Parkinson's.

Dr. Joash Lazarus 00:32:12
There's good evidence to show that early exercise and an appropriate amount and type of exercise can attenuate not just the primary disability, but the degree of secondary disability and its impact. This data was from a group of patients who had stage 3 PD, so symptoms on both sides of the body and were already starting to have some balance and gait problems.

We spoke about the generic effect in which exercise can improve brain function in the general population, Alzheimer's, the elderly population and even patients with depression. But we also know that, in both healthy adults and in PD, one of the molecular changes we mentioned was an increase in BDNF, which may be neuroprotective.

How do we provoke those changes, possibly? Although not done in the same study, if you aggregate the clinical data that has been done to date, we notice that moderate-intensity aerobic exercise at least three times a week, of about an hour duration, has a positive impact on executive function. We know that things like resistance exercise of slightly longer duration twice a week can improve not just executive function, but also working memory and attention.

More recently, there was a large randomized controlled trial of high-intensity exercise looking at two possibilities, either very high intensity — 80% to 85% of maximum heart rate — or more moderate intensity, 60% to 65%. That improved mobility compared to either the moderate intensity or just usual care with medications or physical therapy.

It's a lot to take in, but I will summarize the types of exercise that I think are very practical and the benefits they do have. If you have to sum this up, there's really good evidence that early exercise of moderate or severe intensities — so high-intensity exercise frequently — has a good benefit on cognitive function and mobility in Parkinson's. And that this vigorous exercise, because of the data that we have to date, appears to maybe have a neuroprotective impact, not just covering up the symptoms. We’ve shown that it has a symptomatic benefit and a quality-of-life benefit, but potentially, it could impact the process as well. The evidence for that, of course, comes from people with PD who had regular exercise and had less cognitive decline after one year in a study that was published in 2016. The proof of that will have to be shown in a long-term study that’s prospective, where we look ahead and randomize two groups, like was done in the two medication trials and in the DBS study we discussed earlier.

But this was a really interesting study published in 2018 called the SPARX study. It was a national, randomized, single-blind study. Here, patients were divided into usual care, in which they were really treated with optimized medical therapy. A third of them actually had DBS as well. A second group had moderate-intensity exercise, so the exercise programs were geared toward elevating the heart rate to about 60 to 65% of expected maximum heart rate, which is age-dependent. And, of course, a third group was to elevate the heart rate to between 80 and 85%. The outcome we looked at here was the degree of motor symptoms, that UPDRS score again, at around the six-month mark.

You can see that those who had the highest-intensity exercise had no change at all in the UPDRS score. Those who had moderate intensity had a smaller change, and it was the group that had usual care, the clinically standard of care, that had the highest change in overall symptom severity. This helped establish the case for high-intensity exercise as being really effective early and throughout the spectrum of Parkinson’s disease. There’s another study following up on this called the SPARX3 study, which is the first and largest randomized, double-blinded controlled study in which patients will be randomized to these two groups or just optimal care.

Dr. Joash Lazarus 00:35:53
Apart from just the UPDRS score, a DaTscan will also be used to look at the actual dopamine transporters in the brain, and spinal taps will be done to look at inflammation and the degree of inflammation in the brain as well. So a number of different outcomes are being used. But in addition to pure clinical trials, which provide really good information about whether an intervention is effective, there’s also registry data that we have looked at. This study, for example, included 4,886 people with PD, and almost half of them, 44%, did more than 150 minutes of exercise a week, compared to a fifth of them who did less than that, and 36% who did no exercise.

The important findings to summarize here are that the group of patients who did regular exercise did better in terms of overall physical function. They had less depression, as measured by really well-validated scales, and overall, a better quality of life at the one-year mark. More importantly, compared to those who had poor physical activity at baseline, there was improved cognitive function, which was objectively measured, and also better quality of life, mobility and physical factors one year later. So not only did exercise matter, but the take-home point from this registry data was that the dose matters as well, much like when we talk about medication regimens and brain stimulation, for example.

So we started with a general template and the state of affairs right now as to how we approach a newly diagnosed Parkinson’s patient and how we try to be as comprehensive as we can. But one caveat was that we kind of relegated complementary therapies and things like exercise to later on, after optimizing medication management. Based on the growing body of literature and really good studies that have been done now, it’s provided good impetus for us to institute that much earlier on. There’s good evidence to show that, number one, dose matters, but timing also matters.

Dr. Joash Lazarus 00:37:44
Early high-intensity exercise is definitely going to have a benefit whichever way we phrase that, both in a symptomatic sense — in terms of day-to-day functioning, how patients are feeling and how their experience of disability and function progresses over time — and even more excitingly, the possibility that it could actually attenuate the disease process, which several studies are looking at validating or establishing right now. Moving forward, this is definitely something that will enter our conversations on a clinical basis as to whether, what mechanisms and in what way exercise and different physical therapy programs impact the disease process as a whole.

Putting everything into context, we spoke about how different forms of exercise have been evaluated. They all, as a whole, have some form of benefit across differing subsets of cognitive function, motor function and non-motor function. It’s hard to kind of distill together, but as a summary, a total of 150 minutes per week has been shown to have really good benefit in Parkinson’s patients, and to really get the heart rate elevated. So the high-intensity group, those patients who got their heart rate up to between 80 and 85% of the maximum heart rate, generally did better.

Of course, it’s hard to measure that without equipment or a heart rate monitor, but you’ve got to get a good sweat and get the heart rate up, to feel kind of fatigued at the end of the workout. If you get a total of 150 minutes a week, there’s good reason to believe that’s going to have a positive impact on the disease process. But at the very least, we know without a doubt that it shows some really good benefit in controlling symptoms in Parkinson’s disease. I know there’s a lot of information to go through. I want to leave plenty of time for questions, and I’m happy to take any questions now.

Dr. James Beck 00:39:32
Thanks, Dr. Lazarus. That was a great presentation. I appreciate you giving this information about the importance of exercise in helping to moderate Parkinson’s disease symptoms, even though it may not be clear that it may be stopping the disease directly. But certainly, I think improved quality of life is going to be critical and maybe difficult to disambiguate — significant changes in quality of life and function versus actually stopping the disease, I would suspect. Speaking of that, Joe and Amy have a question that I think is a real fundamental one that many people in the Parkinson’s community hear: What’s the difference between neuroprotection and neurorestoration? I don’t know if you could define that for us.

Dr. Joash Lazarus 00:40:24
Sure. That’s a really good question to try to distinguish, and there’s a lot of overlap between them. Unfortunately, the process involved in Parkinson’s, and the reason we call it a neurodegenerative disease, is that its natural history, its expectation, is that those processes will continue to evolve. It’ll get worse. The changes we see in the brain will get worse. The dopaminergic neurons will die off, essentially, and degenerate, and you’ll have less dopamine. The goal of neuroprotection is to slow that process down, to slow down the rate at which that area of the brain degenerates, the rate at which dopamine is lost, potentially to stop it if possible.

Neurorestoration would be to try to restore, to get back to baseline, the function that was lost. So while a therapy like exercise, for example, may actually slow down that process in the brain, it may not bring a patient back to where they were before the diagnosis, or two or three years ago.

Now, DBS is interesting. DBS has some of the neurorestorative features from a patient perspective because it can completely control tremor and improve their function to close to baseline, nearer to baseline or even baseline levels. But it would be interesting to see whether that overlaps with a neuroprotective mechanism, preventing things from getting worse.

Dr. James Beck 00:41:42
Yeah, absolutely. You bring up an interesting point about DBS, and you highlighted some of the potential benefits of it, especially for people considering it earlier than later. How do you advise your patients to consider DBS? I think in the U.S., a lot of people have had Parkinson’s a while before they get DBS, I understand.

Do you see a trend for people going earlier? I know there have been studies, and you highlighted some of it, but would that be out of the mainstream? Could you say to someone who’s been newly diagnosed and who has a tremor — and this is kind of along the lines of the question that Linda asked — let’s start with DBS? Has that ever crossed your mind, or where does that fit in the recommendations within your practice and your colleagues?

Dr. Joash Lazarus 00:42:40
That’s a great question. When I presented the data early on, the approach I highlighted was the potential positive impact of early DBS, and we defined that as less than four or five years, at the FDA level four years. I’m actually going to take a different approach right now. In the clinic, we really want to focus on interventions and timing that are well established. By well established, I mean a meta-analysis, several years, a decade of research that’s been replicated. We know that it’s very safe and it’s very effective.

When you boil DBS down to those characteristics, which you should because it is a major intervention, then the best approach to take is a minimum of four or five years after symptom onset, and I’ll explain why in a second, and for symptoms that are not adequately controlled with medication. The reason for that is because DBS essentially does exactly what levodopa does without the complications, so with less dyskinesia or no dyskinesia, hopefully, and without the wearing off. So instead of the medication dipping three or four hours later, you have a more consistent response.

But it shouldn’t give you any more benefit than levodopa, with the exception of tremor. Tremor is one symptom where patients who don’t respond to levodopa can rarely respond to DBS surgery. The reason I wanted to emphasize the importance of the timeline being four or five years is that there’s a group of disorders that we call atypical parkinsonism. Without being too detailed here, things like Lewy body dementia can often be hidden in the background of a Parkinson’s disease diagnosis. There are other cousin disorders, related disorders of Parkinson’s, that behave in a different way. Some of them are a different protein that may or may not respond as well to levodopa.

Dr. Joash Lazarus 00:44:24
But the important thing is they all take a different trajectory. They do not respond as well, from what we know, to DBS. Some of them may actually get a little bit worse. It’s important for us to have a good handle on what the exact diagnosis is, and it really becomes apparent around the four- or five-year mark. Patients who looked a lot like Parkinson’s disease after three and a half or four years may unfortunately develop balance problems or problems with vision that point to something called PSP, and those are patients who would not respond to DBS based on current literature. The same is true of Lewy body dementia. Patients may develop hallucinations or cognitive issues.

Jumping the gun and going for DBS too early may unfortunately include patients who will actually do negatively from DBS, number one. And number two, you probably would get very good benefit from medication management for the first four or five years. You won’t see a benefit in terms of quality of life, and that’s the goal — function, quality of life and disability reduction — within the first few years. It’s something I don’t typically broach until that point is reached.

Dr. James Beck 00:45:28
Yeah, understood. It seems like the safer and better approach is to wait because, as we all know, Parkinson’s disease is not a disease where you get a blood test or brain scan and you have PD for certain. Many people in our community have that frustration, and I’m sure you do too, trying to confirm someone’s diagnosis is exactly Parkinson’s and finding the best therapies for them as part of that process.

One last question about DBS. Does it impact other parkinsonian symptoms? People, I think, would certainly hope it would help with stiffness and the rigidity that people experience. What about freezing of gait? Does it help with that? Or any issues with cognition, fogginess? Does it help or hurt?

Dr. Joash Lazarus 00:46:21
The best way to separate the symptoms is kind of motor symptoms, or movement symptoms, and non-motor symptoms. If you look at the motor symptoms, DBS is absolutely, exquisitely effective for tremor and for dyskinesia. Those, without a doubt, generally get very much better and can improve to the point where patients’ function gets better, they’re much happier and they’re doing overall much better from a disability standpoint. Freezing is a little more complicated. The best way to summarize it — it’s an overly simplistic answer, but the best way to look at it — is that if those episodes of freezing get better with levodopa dosing, we call it dopa-responsive, then there’s a good likelihood they would also get better with DBS surgery.

But often, unfortunately, a small group of patients can have freezing even when they’re on. So even when they take the levodopa and the tremor is controlled, and the medicine is kicking in at a high dose, they still freeze. Chances are those episodes of freezing do not get better with DBS, and depending on the frequency, how often they’re happening and how bad the freezing is, that may not be the best treatment option for that patient at that time because they may not see a benefit if they still feel freezing.

The non-motor symptoms are also very interesting. Most of the DBS studies, the outcomes that were followed, in other words what they were targeting, were the motor dysfunction, the very visible symptoms. As a rule of thumb, we always say we don’t try to address the non-motor symptoms with DBS as a whole. In other words, if patients are suffering from depression, we wouldn’t go to DBS as a targeted therapy.

Dr. Joash Lazarus 00:47:55
It is, however, very safe. In the beginning, we would follow very closely cognitive function and mood function, so depression and hallucinations. As exclusionary criteria, we had a kind of high threshold. If patients had a minimal amount of cognitive dysfunction or depression, we would try to lean them away from DBS, but it’s become very clear over the last decade that from a cognitive standpoint, DBS is very safe, especially in patients who have relatively well-preserved cognition. From a mood standpoint, it may not worsen depression, which can be controlled with medication management.

Completely off topic, DBS has also been studied extensively now as a primary therapy for depression, other mood disorders like obsessive-compulsive disorder and even for addiction. Different areas of the brain, different disorders entirely, but just something to look out for.

Dr. James Beck 00:48:35
Interesting. A tool can be used for many issues when it comes to the brain. Moving on to some other questions regarding exercise, I think a person with Parkinson’s wants to know which might be more effective for slowing PD progression: medications, pharmacology or exercise?

I would hazard, from what we just talked about today, to say nothing is really slowing progression that we can definitively say, but it seems like you’re making a good case that exercise is probably one of our best bets.

Dr. Joash Lazarus 00:49:17
Yeah, and I don’t want to phrase it as an either-or paradigm. Many patients will only see the benefits of exercise — in fact, the majority of them — if they reach the high-intensity level, which, if you strictly define it, is 60 to 65% of your heart rate. You’ve really got to get sweating. In order to do that, for a patient with tremor or freezing, it’s only going to be possible if you’re on a good dose of medicine to allow you to reach that. The motor problems really hold back your performance in a workout or in a physical therapy session.

So it’s really the combination that proves best, and that combination is individually determined. Optimal drug therapy in all those studies that are highlighted — there’s no specific dose or frequency that we can reference because it’s really dependent on the patient. The ultimate best treatment strategy is a combination of the two. But I would say that, regardless of the status of the patient, any Parkinson’s patient should include some form of mobility protocol, either exercise, physical therapy or both. And that’s regardless of how much disability you’re starting with, what stage of Parkinson’s you have, whether you have symptoms or not, really. It’s a more consistent form of intervention that we should emphasize a little bit more frequently, I feel.

Whereas the pharmacotherapy tends to be a little, for lack of another word, niche, in that there are certain circumstances, certain very targeted goals and certain targeted effects that we would follow and think of.

Dr. James Beck 00:50:43
Yeah, absolutely. I think your slide was really appropriate. It’s a prescription for exercise, right? And like other medications, you have to take it on a regular basis in order to see an effect.

I guess it gets to the question we’re seeing: the two different heart rates that you suggested from the SPARX study, and there’s a phase three trial I think that’s going to be recruiting soon for that. Do you think there’s a dose response for exercise? When we talk about intense, as you said, 60%, maybe 80%, is that sufficient? And do you have to be on a bike, or is it just a matter of working hard to get your heart rate up?

Dr. Joash Lazarus 00:51:26
Great question. From the first SPARX study, it looks like there is a dose response. It looks like dose in terms of heart rate and total duration more than exercise duration per session, for example. That’s very practically hard to break down. How do you establish a really good dose response? Well, that’s the purpose of SPARX3, which is randomized and placebo controlled. In other patients, it’s been shown that if you get the heart rate up to 80 to 85%, some of the molecular changes — that molecule BDNF in the brain that we spoke about — the amount is increased thereafter.

In healthy studies, there was a new study in healthy athletes, actually, that if you reach that heart rate for as low as 10 to 12 minutes, you can trigger an increase in the BDNF. Then it didn’t matter whether you exercised for 12 minutes, 40 minutes or 50 minutes; the impact on the brain was still beneficial after 10 to 12 minutes. It wasn’t a dose-response curve in terms of time or duration. It was in terms of volume of BDNF, which is intensity. We’re not sure if the same is true or applicable in Parkinson’s, but this study will tell us because we’re segregating both based on heart rate and duration, and different measures.

So it’ll be interesting to see whether it’s purely a function of how hard you work and how much you sweat, or if it’s a question of how long each session is, or both. Does it really matter what type of exercise? Is it a question of stressing the cardiac system enough because this is just a good surrogate of how well the workout is doing? Or, as we pointed out in multitasking and dual tasking, do workouts that include a cognitive task — a great example of that are boxing workouts, and there are several that are well established in Parkinson’s — confer their benefit because of this dual-tasking component more than just getting the heart rate up? There are so many questions to really look at.

Dr. Joash Lazarus 00:53:12
But the takeaway message I think is really important for patients is consistency is the key. Just like consistency for medication dosing, at least three to four times a week and at least 150 minutes, and to stick to something that you really enjoy because that’s really the only way for any of us to be consistent with an exercise program.

Dr. James Beck 00:53:29
Okay, great. I see we’ve got a couple more minutes of your time before I know you have to go and before we’ll have to go on to the closing slides. So let me just ask some quick questions, if I may. Maybe this is not so quick, but Chance asks, how do you exercise when you have problems with balance and you have a risk of falling down? Related to that, should you go to a physical therapist, or should a doctor prescribe your exercise regimen?

Dr. Joash Lazarus 00:53:58
That’s an excellent question. I would say that physical therapists are the experts right now in doing that. It’s an aspect of medicine, an aspect of neurology, that’s been neglected. I’ll honestly admit that even as physicians, we have so many constraints and our focus is often narrowly geared toward the medications, surgery and aspects like that. Physical therapists, especially those who are BIG therapy-certified, are really good at structuring a mobility program. I say mobility because it’s either therapy or then the transition from therapy to exercise.

That’s a very good question because the risk of falling is high, and in high-intensity or stressful exercise it’s going to be even higher. So having guided therapy leading into guided exercise programs is a great way to do that. There’s a paucity of really guided, assistance-driven exercise programs right now. In fact, the Parkinson’s Foundation has an accreditation process that was recently established to look at a couple of boxing programs. One of the criteria there is that there are enough assistants and enough trained, certified help to prevent patients from falling, which means it can cater to more disabled patients, those with a greater degree of motor dysfunction, those who are prone to fall. Expanding our avenue to look at programs like this and expanding access to programs like this is going to be really great.

Dr. James Beck 00:55:17
Fantastic. Two quick questions, and I think I know the answers, but does DBS make exercise more difficult?

Dr. Joash Lazarus 00:55:24
No. It really should make things better, and that’s a good point because it should not exclude exercise. DBS is not this magic bullet to control DBS. It really should draw attention to maximizing our function. So don’t stop exercising after DBS. If anything, really evaluate your exercise program to maximize how much you can do.

Dr. James Beck 00:55:47
And then the last one before you go, and again thank you for your time. It sounds like if someone is able to exercise and get involved in their program, they might be able to alter their medication doses with the help of a physician. Is that what you would expect, where symptoms seem to be better under control and they can then adjust perhaps their medication dosage?

Dr. Joash Lazarus 00:56:09
Absolutely. One of the studies, when you follow patients for six months, those who did consistent exercise either stayed on the same dose or had fewer increases in medication. Our tendency as neurologists, and not just neurologists but as a medical fraternity, is to add medications on, not necessarily take them off. But I think that we can see more and more instances, with things like surgery for sure, but with more comprehensive physical therapy and complementary therapies, that if you have an MDS specialist who’s really attuned to your experience, it’s very possible to start coming down off the medications like we see in other consequences of exercise-related health benefits. Insulin doses gradually decrease.

People come off their cholesterol medicines. High blood pressure medication decreases. Those are all chronic illnesses that are modulated in one way or another by exercise. We said exercise has pleiotropic benefits, including the brain. There’s no reason not to be optimistic that we can at least consolidate, when patients who are on three or four different Parkinson’s medicines will have less wearing off now because of exercise and may not need an adjunctive injection or something like a COMT inhibitor. Those, I think, are very positive goals to aim for.

Dr. James Beck 00:57:16
That’s fantastic. Exercise is the rising tide that raises all boats. Dr. Joash Lazarus, thank you very much for your time.

I really appreciate it. And I want to thank everyone here as well for their time and the audience for listening. I also want to thank again our sponsors, Genentech, the Light of Day Foundation and Kyowa Kirin, as part of that.

On our next slide, we show that we’ve knocked out three of our expert briefings so far this year. We’ve got three more to go. We’ll be taking a bit of a break as we move over the summer and get ready for the impact of physical activity with Dr. Miriam Rafferty in September. But we’ll certainly be thinking about questions that may come in, and we’re here to help as part of that.

We have lots of resources and supports. The Aware in Care kit is fantastic for those who may be going to the hospital, just to help communicate their needs within the hospital setting. We have our library resources as well, of course, as our regular presentations on PD Health @ Home for everyone there. We also have other resources for people who like podcasts: Substantial Matters. I encourage everyone to listen in. For the few professionals I saw who joined us today, we have opportunities for CME. The Foundation is now providing accredited education units for clinicians. We have CMEs and CEUs as well.

And at last, I always encourage people to think about participating in PD GENEration. It’s an opportunity to get an understanding of whether you have a genetic risk, a genetic form of Parkinson’s disease. It’s rare, but this is the first step to knowing and having the potential to participate in clinical trials, which I think will be coming, targeting those with genetic forms of Parkinson’s disease.

Dr. James Beck 00:59:19
Last, we’re here for you in case you have any questions: Parkinson.org, 24/7. We have our 800 number, 1-800-4PD-INFO. We’ve got colleagues standing by who are very experienced at helping to answer questions. If you prefer, you can send it by email Helpline@Parkinson.org.

But before we go, I just wanted to say that your feedback is always important for us. When this Zoom call abruptly stops, a window will pop up on your browser, giving you an opportunity to provide feedback for this webinar. We certainly utilize it, and we share it with our speaker as well. So please take the time to give us some feedback on your thoughts about this expert briefing evaluation.

I wish everyone a good Parkinson’s Awareness Month in April and look forward to seeing everyone at the next presentation come September. Until then, take care.