Parkinson's Disease Highlights 2023

This transcript has been edited for clarity.

Kathrin LaFaver, MD: Hello and welcome on behalf of Medscape. I'm Dr Kathrin LaFaver, a neurologist in Saratoga Springs, New York.

I have the great pleasure to be talking with my friend, Dr Alberto Espay, today. Alberto is an endowed professor of neurology and the division chief and endowed chair of the Gardner Family Center for Parkinson's Disease and Movement Disorders in Cincinnati.

We are here today to talk about highlights in Parkinson's disease in 2023. Welcome, Alberto.

Alberto J. Espay, MD: Thank you, Kathrin. I'm delighted to be with you.

LaFaver: Maybe we'll start off with biomarkers. I attended the AAN meeting in the spring. There was some buzz around the Syn-One skin testing and I know there are also CSF biomarkers. Where do we stand? Is this something that, as a neurologist in practice, I should be doing or ordering for my patients?

The Syn-One Skin Test

Espay: It's a very interesting development. The Syn-One test is a way to quantify the phosphorylated conformation of synuclein. It's a way to determine the extent to which skin tissue contains synuclein in an aggregated fashion. We know that it is a reflection of the pathology elsewhere. Synuclein is everywhere in the body, and it is most accessible in the skin.

This test is conducted by biopsy in three regions of the body: the neck, leg, and then distal leg — close to the feet, essentially. It does two things: It tells us how much of the synuclein in an aggregated state there is and how much degeneration there may be in terms of the nerve fibers that run through it, so it quantifies two different things.

It's interesting because it is the first test that has a very high sensitivity and specificity for the diagnosis of Parkinson's disease, but more importantly, it is helpful to separate Parkinson's from multiple system atrophy, something that prior tests have not been able to accomplish. In fact, it can, depending on the pattern of density of pathology as well as of the relative loss of the small fibers, separate Parkinson's from dementia with Lewy bodies, which, in fact, has been quite elusive in prior efforts.

This is a very effective way of getting to a diagnosis of Parkinson's as the syndrome. Obviously, not necessarily to help us with biologically subtyping the condition, but very important in terms of confirming that we're dealing with a synuclein disease in the form of Parkinson's vs multiple system atrophy vs dementia with Lewy bodies, or vs pure autonomic failure. There is a different pattern for it. These are all the so-called synucleinopathies. I think this is the best test so far, and it's minimally invasive.

LaFaver: How do you apply this? Do you order this in patients early on to confirm a diagnosis or if they don't respond well to treatment? What's your approach to this?

Espay: For now, I suspect that, in specialized clinics that deal with Parkinson's disease, we probably don't need the test in the vast majority of patients if we do our clinical examination and determine that the diagnosis is fairly clear. I think the test might be most used in situations where there is diagnostic uncertainty.

The first type of uncertainty is the one where we determine that someone is slow; we might not say slow and parkinsonian, but perhaps a non-parkinsonian type of slowness. This could be one area in which the test could be very helpful. Though in this case, it would be very similar to what we currently do with DaTscans, where we determine whether there is a dopamine deficiency; that would fulfill the same purpose.

What I think is most interesting is those situations where we have uncertainty among the parkinsonisms, particularly if we think that a patient with what we have thought is Parkinson's disease has accrued features of what might appear to be an evolving multiple system atrophy. In that situation, of all the tests that we currently have to try to distinguish multiple system atrophy from Parkinson's disease, the skin biopsy might become one of the early ones to think about, just by virtue of how sensitive it is for picking up the difference.

In this situation, this could end up changing how we approach diagnostic workup of these patients in a manner that could turn out to be quite relevant. Does it make a difference in terms of treatment? At the moment, that might not yet be the case, but it's always important — at least, if nothing else, then for prognostic reasons and also for understanding what thresholds of levodopa therapy to use, for instance — to know whether we're dealing with Parkinson's disease vs multiple system atrophy.

Certainly, that applies to the distinction between Parkinson's and dementia with Lewy bodies, which are conditions that can look very similar early on. This would be another way to recognize the difference between individuals with these two diseases.

The Seed Amplification Assay

LaFaver: Very good. Certainly, it is a useful tool to have in our toolbox and less invasive than a CSF biomarker test. Thank you for that.

Espay: There is another test that people may have heard of, which is the seed amplification assay. The Syn-One test is quantitative. It allows us to quantify the amount of protein, the load of protein that's in an aggregated state. The seed amplification assay is qualitative. It only allows us to answer yes or no: Is there aggregated synuclein in this tissue I'm testing? It doesn't tell us how much there is.

In the Lancet Neurology paper that made the rounds around the world and was hailed as a breakthrough, we know that particular study showed that there was no correlation between test positivity and any type of parkinsonism, whether it was predominantly motor vs non-motor, whether it was REM behavior disorder or not. There was no correlation between it and severity of disease.

There was no predictive ability to determine what kind of outcome patients would have, and it would, therefore, not be helpful for the purposes of monitoring response of therapy or for subtyping. I want to make sure that these two tests are kept quite differently in terms of how we think through them.

However, there are efforts to making it a central component to what's going to be referred to as the biological definition of Parkinson's disease. I'm a little concerned about that since it's simply a test of pathology but in no way reflects any underlying biology.

What Might GLP-1 Receptor Agonists Mean in PD?

LaFaver: That's very helpful — to not throw all the biomarkers in the same box, for sure.

Let's switch topics. I've been kind of following the link between diabetes and Parkinson's this past year, and I was curious to hear your thoughts. The GLP-1 receptor agonists are getting much more popular in diabetes treatment. What do we have to look at here? How does this influence our potential ability to help patients?

Espay: It's a great question and it's an evolving story. We've known for a number of years that individuals who had diabetes and were treated with GLP-1 receptor agonists had a lower incidence of Parkinson's. We're talking about a 30%-40% reduced incidence of later development of Parkinson's.

There is this connection at an epidemiologic level that the use of this particular therapy could have disease-modifying effects. Now, two things are important to recognize here. The first is that forever we've had what's referred to as the pharmacoepidemiology disconnect.

That means findings at an epidemiologic level that would suggest that there is a modifying effect of an intervention, because a relationship at a population level, do not translate into actual disease modification once the trials are done. There are many, many examples of this. In fact, it's inevitable that we have a connection between two variables at a population level that speaks about lower risk. Lower risk does not translate once the disease state is established into a slower progression.

The best example of that is, perhaps, urate. Low urate is clearly associated with a great risk for Parkinson's — high urate, lower risk. It was only logical to test the hypothesis that increasing urate would, in fact, slow the progression of Parkinson's. That was tried, to no avail. There was no difference. This pharmacoepidemiologic disconnect has been universal in our history.

We've never been able to translate epidemiologic findings into disease-modifying treatments. That then connects to the second point, which is that we know Parkinson's isn't a disease; it's a syndrome. Therefore, there are many biological subtypes that are surely associated with what we today call Parkinson's disease.

Is there a subtype, in which insulin resistance is not a downstream phenomenon, but an upstream abnormality, something that actually drives the disease subtype in individuals who have a particular problem with the mechanisms about which glucagon-like receptors have a role? We don't know.

If there is to be an effect that emerges in the trials — and there are preliminary results of one of the trials conducted in France that suggest that a change in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) such that the motor severity is lower at the end of the study — it would have to be symptomatic. It would not be disease modifying. We'll have to figure out what that means, of course.

Disease modification does require us to pair the therapy with the mechanism of action at play in the recipients. That mechanism of action must be pathogenic, not just a consequence of many processes, but at a cause of one specific subtype. We don't know where that is.

I have asked colleagues who are leading these studies whether they are recruiting for these studies with a specific assay that determines the extent to which an insulin resistance marker in the brain would be indicative of individuals particularly vulnerable to this therapy. That's not the case.

The good news is that some studies have been preparing themselves for what is referred to as the postmortem of the study, which means the study fails but the assumption is that there surely will be people who benefit from this, and then we'll need to figure out who they are. With biospecimens biobanked — blood, particularly CSF, maybe other tissues — we could potentially determine whether those who are going to be in that category of responders might, in fact, be individuals who in subsequent development we could screen for, and then potentially do another analysis, enriching for those in whom we think that the particular mechanism is most relevant at a pathophysiologic level.

It's an evolving story. I think that there will be much more to learn, but I'm worried. We've had many therapies with fantastic mechanisms of action that have failed, largely because it's not the kind of mechanism we later have recognized to be quite as dominant in one subtype. It seems to be a common expression, right? We know that even 40% of patients with Parkinson's have low urate. Well, that's too large a slice of the Parkinson's pie to imply that it's somehow pathogenic in those 40%.

Continuous Pump Therapy

LaFaver: Thanks for these words of caution. To close out our conversation, let's talk a bit more about therapeutic updates. This is a big topic, but one thing that you have been particularly interested in is the continuous pump therapies to simplify medication administration for people with off symptoms. What are we looking at in that sphere?

Espay: Yes. In the next year or so, there will be a total of three subcutaneous infusion systems. Two are based on levodopa. One of them is a levodopa precursor called false levodopa, and one of them is apomorphine infusion. They are at different stages of review. All studies have been concluded very much with positive outcomes. I think, by and large, the results are comparable among the infusion systems.

One is produced by AbbVie. One is produced by NeuroDerm, now owned by Mitsubishi Tanabe. The other one is owned by US WorldMeds, which is now owned by Supernus. These three infusion systems should help, particularly, those individuals who have motor fluctuations that are associated with significant off/on changes and perhaps unrelated dyskinesia, for whom we are unable to optimize the oral therapies to such extent that we can extend the on without bringing difficulties with dyskinesia or having other problems.

We often have said to our patients that levodopa is to Parkinson's what insulin is to diabetes, but we've never really brought that metaphor to the next level of development, which is to say an insulin-like infusion system for Parkinson's. We finally have that. There have been many, many attempts in the past. Levodopa is not a molecule that is easy to deliver in transdermal form.

The subcutaneous infusion is now panning out to be very good and the level of benefit is quite significant. With all the challenges of double-blind, double-dummy clinical trial designs, the interventions have achieved close to 2 hours of extra on-time. This is good on-time, meaning the time that individuals have the best possible response where they are without dyskinesia or with nontroublesome dyskinesias, which is the good on that we want to have our patients on. It's really quite helpful.

This infusion systems are likely going to help in those patients in whom we might also be thinking of deep brain stimulation or other surgical interventions. For them, this might be an easier step earlier than that. Perhaps it is possible that in many patients who go into an infusion system, an advanced surgical intervention might not be needed.

It's a way to start moving toward a more physiologic restoration of dopamine function in the brain. I think it's going to be a welcome arrival.

We're probably a few months away from having the first approved. There have been some issues at the regulatory level for the infusion systems. Once they are approved, I think that they are going to represent an important resource for patients to have an improvement in their overall quality of life.

Individualized Parkinson's Treatments

LaFaver: Absolutely. I see patients every week who could probably benefit from these treatments. For me personally, it's exciting to see more mechanisms being explored. There's a large amount of work going on with neuroinflammation in Parkinson's, for recognizing more overall lifestyle factors and wellness being important. There are many developments. Anything else that you want to highlight, that you are excited about for the coming year?

Espay: The most excitement that I get these days is really about the biomarker development program moving into an area in which we're finally becoming congruent with what we say. We've said to people forever that Parkinson's isn't a disease. We tell our patients, "Do not compare yourself to anyone else. You have your own brand of Parkinson's. You're blazing your own trail."

We follow that up by saying to be hopeful because one day we'll have a biomarker of Parkinson's. Also, we'll have a treatment that slows Parkinson's progression. The savvy patient would say, "Well, you just said to me that I'm unique. Are you also saying that there will be a treatment that will be equally effective for everyone?"

Of course, we're finally walking the walk when we say, "No; you're unique such that now we are beginning the process of identifying what it is about you, not what connects you to others with the same diagnosis, but in fact, what makes you different from others." This is the platform that the field of oncology created to individualize the molecular biological sources of disease.

In the future, we would be able to tell a patient with Parkinson's, "You have Parkinson's." Just like an oncologist would say to a patient being diagnosed with a kind of cancer, "I don't know what that means. I would have to do certain studies in different tissues to be able to determine what is it that you have, and then to be able to define what treatment to apply to your disease."

"Meanwhile, here's levodopa to make you feel better." I think that would be a more honest conversation. We began that process, but like all changes in history, they are going to take much effort. They're also uncomfortable and inconvenient, but it's the right thing to do. We're moving in that direction and this is very exciting in many, many ways.

LaFaver: Very good. Thank you for all the work you're doing in this really important area. With that, we'll part. Thank you again, Alberto, for this overview. Thanks to all the viewers.

Espay: Thank you so much, Kathrin. It's been a pleasure, as always, being with you.

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