Genetic testing in deep brain stimulation for Parkinson's disease

In this inaugural episode, we have the pleasure of speaking with Dr. David Arkadir, Head of the Parkinson's Disease and Movement Disorders Unit at the Hadassah Medical Center in Jerusalem, Israel. And Dr. Saar Anis, a Movement Disorder Fellow at the Center for Neurological Restoration at Cleveland Clinic in Ohio, the United States of America.

So welcome and thank you both for joining us.

Dr. David Arkadir: Thanks for the invitation.

Dr. Saar Anis: Thank you. It's great to be here.

Dr. Michele Matarazzo: Today we'll explore the role of genetics and genetic testing in deep brain stimulation for Parkinson's disease. This is an evolving field with increasing relevance for [00:01:00] clinical practice and patient care.

This episode was developed in collaboration with Dr. Gian Pal, a member of the Scientific Issues Committee of the MDS, and I want to acknowledge his collaboration and his contribution.

Let's start with the first question. Again, genetic testing is increasingly becoming part of our routine clinical practice, bringing us closer to what we would like to call personalized medicine somehow. Now, David, to set the stage, could you give us an overview of what we currently know about the relevance of genetics and genetic testing to DBS for Parkinson's disease?

Dr. David Arkadir: Yeah, so say a few words about genetic testing generally. So we know by recently recent studies that were published that up to 10% of PD population worldwide are positive to mutation in a gene name, GBA1, and about up to 3% in a gene name LRRK2. We have other genes as well, but we'll dedicate most of the [00:02:00] talk to those two genes.

In some populations, the percentages as quoted are higher, like in the Ashkenazi population, and probably when it's regarded to DBS or adult advanced therapy, probably there is over representation of people with monogenic PD. That are candidates for those advanced therapy. So those genes are highly relevant.

Not just for DBS was also for other advanced therapies. We also know that without even when it's not related to DBS or on average, you can never say about the individual, but on average. So people with mutation in GBA1 has a worse prognosis than people without mutation or with mutation in LRRK2.

People with GBA1 have more tendency to develop neuropsychiatric issues, cognitive issues. Also, the motor disease is probably more aggressive, a [00:03:00] faster increase in the anti PD medication. We know also that in the short term, the DBS is successful for all good candidates, so we expect DBS to improve the motor fluctuation and enable us to reduce medication, especially if the DBS is targeted to the subthalamic nucleus.

What we know about the long term of DBS.

For the different mutation. So we know that for LRRK2, probably the long-term prognosis is better than for GBA patient develop faster cognitive issue and and the axial issue, which are dopamine and stimulation resistance are more aggressive in the yields following DBS the main question, which is I think the issue of this podcast is, are we to blame, or does DBS STN accelerate those cognitive deterioration that is [00:04:00] observed in GBA? And this is still an impending question.

Dr. Michele Matarazzo: Well That's that's actually one of the most important points. I think here and that we will have to discuss. Let me turn this question to Saar actually. David was already mentioning this focusing on patients who are carriers of GBA1 mutation. What is the current evidence and David was already raising this very important point about the possible risks of especially the cognitive part and specifically in this subset of patients with this genetic mutations.

Thank 

Dr. Saar Anis: you, Michele. So current evidence suggests that GBA1 carriers get similar motor benefits from DBS as non carriers, including less dyskinesias, fewer motor fluctuations, and a reduced need for medication. But there are a few important studies, like those published by Avenali and Valente a year ago and Gian Pal and Christopher Goetz a couple of years ago showing that GBA1 [00:05:00] carriers tend to experience faster cognitive decline after DBS.

The extent of cognitive decline may depend on the severity of the GBA1 variant with mild or severe neuropathic variants linked to greater impairment, for example, versus risk variants. So, GBA1 carriers also seem to have a higher risk of orthostatic hypotension and psychotic episodes after DBS. This finding definitely raises concerns about the long term cognitive effects as Dr. Arkadir said of DBS in GBA1 carriers. But at this point, I think we cannot say for sure. If DBS actually speeds up cognitive decline, or if it's just a natural course of the disease in people who are already more at risk. So the reason for that is the lack of methodology some randomized controlled trials and well matched comparison groups of patients who did not get DBS.

It's [00:06:00] hard to separate the effects of the surgery itself from the impact of genetic conditions. 

Dr. Michele Matarazzo: So that's, those are very good points and David, I don't know if you want to add something to this, but I will make you the following question, which is knowing all of this do you routinely test the GBA1 mutation in your clinical practice prior to recommending the brain stimulation?

Dr. David Arkadir: So currently we are not doing it as a routine. First, as Saar said so we still don't know what to do with the answer, how to explain patient about positive finding. The indication for DBS is motor fluctuation with relatively preserved cognition. So if the patient is fulfilling those criteria, we are not sure what to do with the positive GBA answer.

The question whether accelerated cognitive impairment can cause by the DBS is still pending. There are a nice paper by Pal, but there is also other contradictory evidence so this is why we are not [00:07:00] routinely sending patients for a GBA testing. Still I would like to say Three different comments on this general comment.

So first, if I'll send a patient to a genetic test and then we'll find him to be positive for LRRK2 m utation. So this is in a way reassuring because we know that LRRK2 have a better prognosis for the long run with DBS and without DBS. So this is one of the command. The second, so still I think GBA can be incorporated in our decision when you have a borderline cases, like people with a borderline age.

People with individual with borderline cognition, which you're not sure whether to recommend an operation or not. So maybe GBA can be included because you know that maybe people with GBA will deteriorate. With or without the DBS and maybe it's the risk for the operation is not justified.

And maybe the third comment is what I said [00:08:00] until now, it's regarding our clinical routine. Regarding research, it's important to test patient, to learn, to accumulate experience, so we'll be able to address those questions better in future podcasts.

Dr. Michele Matarazzo: And actually getting back to not the future podcast, but the previous podcast Saar was mentioning before the paper published by Avenali and colleagues and Maria Valente, and this was featured on this podcast. So I invite all of the listeners to go back to that episode. I think it was.

About a year ago when it was published on the JNNP. So that interview is also available in case you're interested. Now going back to the interview and and moving forward. There, there is one thing that was mentioned that I think we can discuss a little bit more about, which is apart from the importance of having or not a mutation in a gene. Not all of the mutations are the same. And specifically for GBA1, this is particularly relevant [00:09:00] now would you like to elaborate a little bit more on the evidence if there is any, or what is your opinion on having a mild mutation, a risk variant, or a severe mutation in GBA1?

Maybe also to explain a little bit what those are and what relevance this might have for DBS.

Dr. Saar Anis: Yeah. So I think this is a great question. And I think this is one of the most unanswered questions that we have. And, looking ahead, I think that research should also focus on that specific question, whether different, genetic variants within a gene, for example, GBA1, but not only, right?

What about LRRK2 and other genes? So this is an important question, but I still feel like we're at the stage of first understand better the impact of each gene and then dive and see specific ones, for example, mild and severe variants, which [00:10:00] can cause Gaucher, right? Or versus risk variants, which were found to increase the risk for Parkinson's, but not necessarily related to Gaucher.

So the question is, are those different variants have different effect on DBS outcomes? And as I mentioned, I think David, please correct me, but there are not a lot of papers, focusing specifically on specific variants, but for example, Gian Pal focus on that and did specific analysis and saw actually differences between different variants.

And actually I think it's a very important question because we know that specific variants might affect the disease, right? Severe GBA1 variants might cause a more severe disease and progression. So the question arise whether DBS might affect those patients even worse. David, what do you think about that?

Dr. David Arkadir: [00:11:00] Yeah, I agree. I think it's an interesting question. We know the genetic history of severe mutation is worse than those of milder mutation in the GBA. Also, this is, there is some exception, like the E326K mutation, which is a mild mutation. But it's more associated with cognitive issues. But as Saar said, the stigma is still in the stage of debating whether GBA should be taken into account in DBS.

And we are still not in the stage of fine tuning of which type of mutation is associated with more cognitive risks.

Dr. Michele Matarazzo: Yeah, and even more complicated and I'm pretty confident there is no evidence about this regarding DBS, what about the interaction between different genes? Let's say LRRK2 and GBA, because we know that there is an interaction between these two genes and clinical 

Dr. David Arkadir: consequence... 

Before, and yeah it's endless. So we have to go by gene before everyone wants to split between mutation...

Dr. Saar Anis: I would, I would actually like to talk about it later on, maybe. 

Dr. Michele Matarazzo: Okay. Well, Let's talk about, let's talk about LRRK2 a little bit [00:12:00] now. Saar what do you think that LRRK2 mutations, those are also being explored as predictors of DBS outcomes in Parkinson's disease? Do you want to discuss the current understanding on how mutation in the LRRK2 gene might influence the results of DBS?

Dr. Saar Anis: I think that this is maybe easier topic to discuss compared to GBA1 based on current evidence, including a great meta-analysis done about five or six years ago, published in JAMA. And even a recent Israeli study that we published a year ago. In PRD about LRRK2 PD patients, it seems that they benefit from DBS just as much as those with idiopathic PD.

They respond well to both dopaminergic therapy and DBS and there's no increased risk of cognitive decline as far as we know or psychosis after the procedure. Of course, this is in contrast to GBA1 carriers, as [00:13:00] we said, but in fact, some studies even suggest that LRRK2 PD may progress slower compared even to idiopathic PD, which could mean even a better long term outcomes with DBS.

That said, there haven't been any randomized control trials directly comparing DBS outcomes in LRRK2 carriers. So we still need more research to understand any variant specific effects. But based on what we know so far, I can say that LRRK2 PD patients remain strong candidates for DBS. 

Dr. Michele Matarazzo: Great. And David, what do you think about this? Do you agree with the, with 

Dr. David Arkadir: this?

Yeah, I generally agree. I think with the LRRK2 the it's simpler. The overall, the disease is more benign. So if you operate them at the stage of the need operation because of motor fluctuation, probably they have more years to benefit from the operation generally. There are evidence for there, here and there.

I agree with Saar, there's nothing methodologically, constructed, but that's probably the [00:14:00] benefit is lasting for longer. And then it's reassuring when you're someone has LRRK2. 

Dr. Michele Matarazzo: Well, now let me ask another question which is. What are some of the ethical and clinical challenges in integrating genetic testing into the decision making during the whole process of, of suggesting DBS for a specific patient. And maybe if there are some specific things related to those genes we've been talking about more, which are GBA1 and LRRK2.

So I think that also there is an ethical component to all of this, right? 

Dr. David Arkadir: Yeah,

I think the main ethical issue is that you don't know when we have a question that it's there on the table. We have an elephant in the room and you don't have an answer what, how to refer. So, should we refer patient to, to gene testing when we don't know I'm sure we have what to do with the results?

How much data, how much we should share with the patient when we ourself are not aware of the [00:15:00] evidence. This is, I think, the main issue. I will say the person I'm trying to openly discuss patient and to let them know that the question is on the table.

But it's also ethically easy to give the patient all the information and to expect him to be opinion about whether to go to the operation or not, and just to forget our role that we have to in the end to give some recommendation. We are treating physician.

We know the limitation of existing data. We know the natural history of the disease. When you have patients in most cases, we know we can see how aggressive is PD. We can expect what will be happening in the future. So based on our experience and data. So in the end, we have to share with the patient our personal recommendation.

And this is problematic when you don't have enough data to rely on. So when I have a patient, if he's a good candidate and he asked me to share my opinion telling the that with this small [00:16:00] asterisk that there is a raised question regarding accelerated cognitive issue following DBS in GBA PD that my recommendation, if he's an ideal candidate to go for it.

Dr. Michele Matarazzo: But you will still disclose to the patient that there might be some suggestion in literature that this might accelerate the cognitive

Dr. David Arkadir: Yeah, I share it with the patient, each patient want to hear, some patient want to discuss it more. Some patient just asking for a personal opinion, but yeah, I will always share if the patient is known the genetic status, and as you said, today, many of the patient know their genetic status.

Dr. Michele Matarazzo: And Saar, do you have the same approach?

Dr. Saar Anis: Yeah I think that this is maybe the biggest issue that, the ethical component of this. And I totally agree with David. But basically, I have to add something about, I feel like. the question is, are we, as physicians and movement specialists, are ready for that? Are we ready [00:17:00] to deliver to the patients that carry those mutations the right message about the impact of these genetic mutations about their outcomes?

And each one of us has own opinion, and maybe our opinions are different. So I think that an important component would be to actually educate providers. In order to improve ethics when we deliver a message, sometimes we, it's easy to say that levodopa, improves motor symptoms in Parkinson's, right?

Because there's so much evidence, but informing patients about genetic results at this important stage of disease, it's huge. And I'm not talking even about, underserved populations, right? That they have less, access to genetic testing and less, opportunities.

And so I think it's important to discuss ethics, right? And it's important to put it on the table and educate ourselves and our patients in the right way.

Dr. Michele Matarazzo: So a lot of work to do. And now talking [00:18:00] about this, looking ahead, what areas of research do you both see as most promising for understanding the interplay between genetics and DBS in Parkinson's disease? David, you maybe want to start

Dr. David Arkadir: Yeah. So I would say that, now when we operate the patient, it's usually those are patient are cognitively fine with motor fluctuation. So in the majority of cases, the life expectancy is decades.

 so, And we still they can live 20, 30 more years even in some gene mutation, even more after the procedure and still 30 years after using STN DBS and many years of experience with a continuous dopaminergic therapies that were more experienced in Europe and a bit less in the States, but still a decade of more than a decade of experience in the States.

We still today don't know what is the best way. What is the best advanced therapy or maybe it's a conservative therapy to keep our patient mobile for as long as we can and we speak about [00:19:00] decades and to give them the best chance to keep the cognition for as best as they can. So it's still an open debate.

It's still an open issue after so many years of using those advanced therapies. And now with the new guy in the block, which is the false levodopa false carbidopa. So this question is even becoming more harder. So I think as a community of the MDS, we have to establish a line of research, a collaboration.

To try to methodologically and systematically accumulate data that will answer those questions in patients with GBA1 or without GBA1 mutations. So this is an open question generally, and of course, when you come to a genetic background, so it's become even more complex. All those data have to be accumulated.

This, I think, the long way is the only way in the end.

Dr. Michele Matarazzo: And Saar, what do you think? So David was mentioning that we have to reshape [00:20:00] the whole scenario of how we approach the advanced therapy for Parkinson's disease patients in a more personalized manner, right?

Not only genetics, also the clinical situation, maybe other biomarkers that could be interesting. So what do you think of all of this? And obviously more specifically of how the genetic will impact these decisions.

Dr. Saar Anis: Right. So a few things to say. First, I think we need some long term cohort studies. It's very hard to do a randomized control study regarding DBS and genetics, but we do need more as David said, multi center studies, tracking patients with GBA1, LRRK2, et cetera. So this is very important, and I think we're trying to do that.

But I also envision, other directions. I think that AI driven models like machine learning approaches analyzing genetic, but also motor [00:21:00] and clinical data together. And as you said, Michele, maybe biomarkers, right? SAA alpha synuclein skin biopsies. There's so many data right now coming through.

So using AI driven models to reveal patterns. That we might miss as physicians. I think this is a very good direction moving forward, not relying solely on one of those. Another direction I thought was, and we talked about it earlier, what about patients that have GBA1 and LRRK2? Yes, they are rare, but they are, they are patients.

And I think that another interesting direction would be to focus on polygenic risk scores. Because, and David, I know David for years, and I know he's saying that he has a lot of experience with those kind of patients. And he told me once or twice that, he has some patients with severe GBA1 mutations that, did well.

And he has, other patients who did less well. So the question is, can we rely [00:22:00] just on the variant itself? Or should we look at the whole landscape of a patient. And if we'll do that we could capture, more information and maybe it would inform us better. So I think polygenic risk scores is another important direction for research about DBS, and genetics.

Dr. Michele Matarazzo: So all of this is obviously very complex. Only look in one gene and what's the role of that gene or that mutation within a gene where the DBS is already complex, but mixing with other genes, the interplay between different genes and putting this within the scenario of a patient with all the things that might happen to a patient, the age the treatment is received and so many other biomarkers that are coming up makes it very complex. So I really hope that you two who are very active as a researcher in the area have a lot of time and energy to carry out all of this research and maybe as you were discussing about [00:23:00] collaboration I guess you're already collaborating between each other.

And that's definitely the path forward because now we need to gather a lot of data to finally have some answers, 

Dr. David Arkadir: Yes, definitely. just, We just started.

Dr. Michele Matarazzo: yeah.

Thank you very much. Dr. Akadir, Dr. Anis thank you both for this insightful discussion. I really enjoyed it very much. Your expertise sheds light on the very complex, but increasingly important aspect of DBS and advanced therapy in Parkinson's disease. And to our listeners, thank you for tuning in to this special episode of the MDS podcast.

Stay tuned for more discussions in our new series in collaboration with the Scientific Issues Committee And goodbye to everyone.

Dr. David Arkadir: Thank you. [00:24:00]