Deep brain stimulation for GBA-related Parkinson's disease: is it a reasonable option?

[00:00:41] Prof. Enza Maria Valente: Hello, everyone. Thank you for the invitation.

[00:00:44] Dr. Micol Avenali: Thank you, Michele, for the kind invitation.

[00:00:47] Dr. Michele Matarazzo: My pleasure. So let's start with some background. Enza Maria, Parkinson's disease is a common neurodegenerative disorder, but could you briefly explain the significance of GBA variants in PD?

[00:00:57] Prof. Enza Maria Valente: Yes, sure. GBA [00:01:00] discovery has been really a great revolution in the genetics of Parkinson's disease because this is, on one hand, a very common risk factor for Parkinson's disease. And in particular, heterozygous variants in the GBA gene are found in up to 10, 12 percent of PD patients worldwide with frequencies that are even much higher in certain populations.

And this is regardless of age at onset and family history. So we are talking about every Parkinsonian patient and a frequency of about 10%. It's really important. If we look at more specific sub cohorts, such as early onset patients, these frequency gets even higher in our Italian cohort, up to 20 percent of patients with an onset below 45 years have a GBA heterozygous variant.

So this is an important risk factor, but [00:02:00] it also impacts significantly on the risk of developing Parkinson's disease and also on the outcome of the disease because it is associated with a much higher risk of no motor features, cognitive impairment, disautonomia. psychiatric features. So it is important to know about carrying these variants for the prognosis for the outcome.

And also it is important to choose the best treatment for these patients. And this is why there is so much research on this topic nowadays.

[00:02:34] Dr. Michele Matarazzo: Interesting. Micol, could you give us a quick overview of deep brain stimulation and its use in Parkinson's disease? What are the main indications and maybe also some risks or drawbacks of DBS?

[00:02:45] Dr. Micol Avenali: Yes DBS is a good therapy for patients with Parkinson's disease, is considered now a days are symptomatic therapy of these patients with important clinical benefits [00:03:00] in particular on term or motor symptoms. Dyskinesias wearing off and on off symptoms. But there are some literature that describe that in some patients with DBS stimulation, in particular with the STN target, there is a worsening of cognitive function.

In particular, last year was published a paper in Annals of Neurology that showed that people with Parkinson's disease and GBA mutations have a worse clinical cognitive outcome over time. So in this view is very important to understand if DBS could be a useful therapy also for patients with genetic mutations.

[00:03:48] Dr. Michele Matarazzo: Great, so probably that's the reason why you decided to do this study, right?

[00:03:52] Dr. Micol Avenali: Yes, of course. 

[00:03:54] Dr. Michele Matarazzo: Now, you approach this research? I mean, it's a very complex methodology, especially [00:04:00] considering that the number of subjects that you included is very high. How did you achieve this?

[00:04:04] Prof. Enza Maria Valente: Yes. And you're right. It's not easy to collect these large cohorts. And this is a good occasion to present the work that we're doing in Italy to collect a larger multi-center cohorts of patients with Parkinson's disease. And this is an effort that has been coordinated by the network for neuroscience and neuro rehabilitation of the Italian Ministry of Health, which created the so called National Virtual Institutes.

And in particular, within the National Virtual Institute of Parkinson's disease, where we have gathered main research centers that in Italy work on Parkinson's disease and the effort of these centers. There are now, I think, 16 different centers from all across Italy participating to this network is to create a homogeneous cohort of patients with a REDCap based database with a [00:05:00] longitudinal collection of clinical data that is done in an harmonized way and also harmonize the strategies for genetic testing and collection of biomarkers and for a subset of cases imaging.

So we're really making a big effort in this and it's not easy, to develop these databases, but it's already paying off because from this database, we were able to select this large cohort of nearly 300 patients who have underwent DBS and all these have been tested for GBA using common methodology that has been optimized within the network.

And these led to have a significantly large cohort to perform all the comparisons regarding motor and non-motor features in these patients follow up is not as we wanted for all cases. We didn't have a five-year follow up for all of them. We are definitely continuing the inclusion and the database of longitudinal data in [00:06:00] order to obtain longer follow-up information for these cohorts.

[00:06:03] Dr. Michele Matarazzo: Wow, this is quite an effort and I'm really excited about the results that it will generate in the future. So let's wait for also more studies with this very interesting cohort. Now, Micol, let's go back to you and let's talk about your key findings. So what were the main results? What did you discover from this cohort?

[00:06:21] Dr. Micol Avenali: Yes. Thank you for this question. In this study, we collected 365 patients with DBS. 20% of them have a mutation in GBA and 73 of these patients were collected in this study. What we observed that at the baseline, so in the evaluation prior to the DBS implant, we observed that these patients was similar in terms of clinical features in particular with similar motor symptoms except for the prevalence of dyskinesias and orthostatic hypotensias that was higher [00:07:00] in people with GBA mutations. After one year from surgery, we observed that people with GBA-PD, and the non mutated DBS patients have an improved motor symptoms with the significant reduction of dyskinesias, on-off phenomenon, and warping off, and also of non motor symptoms, in particular the impulsive compulsive disorders.

After the three year of follow up, again, both cohort have a similar good clinical outcomes in terms of motor controls. But if we observe on cognitive side, we observe that the score of cognitive Mattis score is reduced in people with GBA PD. But if we observe the clinical outcome of dementia after five years from DBS, only 25 percent of [00:08:00] GBA PD patients develop dementia at five years, but we have also considered the disease duration of this patient that is almost 15 years from onset. 

So in this study, we confirm that GBA PD have a poor cognitive clinical outcome over time, but the DBS can also use in these patients for improve their quality of life, their motor symptoms, and with satisfactory controls of also dyskinesia's wearing off phenomenon over time.

[00:08:38] Dr. Michele Matarazzo: So you conclude that dementia is a consequence of PD progression rather than a consequence of having the DBS implanted? Is that what you're saying?

[00:08:47] Dr. Micol Avenali: Yes, it's a very hot point, but in this study we just can see that the GBA patients have a poor cognitive outcome over time. [00:09:00] What we would like to look in the future studies comparing GBA patients with and without DBS to see if over time the DBS could impact on the cognitive decline or not.

[00:09:13] Dr. Michele Matarazzo: But your best guess would be?

[00:09:15] Dr. Micol Avenali: GBA...

[00:09:16] Prof. Enza Maria Valente: Well, that's difficult. That's difficult.

[00:09:19] Dr. Michele Matarazzo: That is difficult.

[00:09:20] Dr. Micol Avenali: We think that maybe the GBA itself is responsible of the cognitive decline, but we need more data and more longitudinal studies to confirm.

[00:09:31] Dr. Michele Matarazzo: For answer the question in a definite way, for sure, you would need a placebo or a sham control trial, right? Because even the selection of patient that are candidates or not for DBS it's already biased for jumping into a conclusion.

But, as you're the experts here, I just wanted to know what you think about this.

[00:09:46] Prof. Enza Maria Valente: Yeah, and I think we need to be very careful because people are really on the lookout for these answer. And there are, I would say, 2 different lines of opinion regarding the opportunity or less opportunity of [00:10:00] performing DBS in GBA patients. And so we need to be careful in giving bold statements at this time, but definitely more studied and more controlled, studied as you suggested are needed because I mean, it's really a matter of looking at the glass half empty or half full, and even if we found a higher proportion of cognitive decline in our GBA patients who underwent DBS. It is also true that 75 percent of them performed so very well after 15 years of disease with no cognitive decline and really had a great benefit.

So it is important to consider both sides and we will definitely carry on further studies on this topic. 

[00:10:40] Dr. Michele Matarazzo: Great. That's quite significant. One important question also looking at previous studies is whether different GBA mutations and genetic variants are related with different outcomes risks when undergoing DBS. Could you separate the risks of different mutation or types of mutation? Let's say the mild, severe and the genetic variants.

[00:10:59] Prof. Enza Maria Valente: [00:11:00] Well, we attempted to do that. Obviously, numbers were a little low, okay, to do a robust statistical analysis. We didn't really observe major differences among groups, but we are now trying to expand the cohort and combine with other cohorts and international collaborations to get some more reliable results.

It is also very important to say, Michele, that the current classification of GBA variants, it's probably not the best one to apply to Parkinson's disease. We inherited this classification from Gaucher and probably it doesn't really divide the mutations in the classes of proper severity, like we've seen a lot of clinical variability among patients who carry mild variants, for instance.

So we probably need some better way to classify GBA variants and there is a lot of research ongoing on this as well. So more [00:12:00] to come on this topic also.

[00:12:02] Dr. Michele Matarazzo: Great. Now what about the difference between different brain targets for the stimulation? Do you think this could have an impact? Like STN would have a different profile when compared to GPI or what do you think?

[00:12:13] Dr. Micol Avenali: Of course, it's another point to look at in these patients. In our study, we have just a minority of patients with GBI implants, so the comparable was not possible. But of course, it would be very interesting to look at the different target in this population, in particular with GBA, maybe could be an indication to use different target in this kind of population.

[00:12:39] Dr. Michele Matarazzo: Absolutely. And how do you think these findings impact the approach to treat Parkinson's disease? Do you think we should genotype all of the patients undergoing DBS? I mean, does the genotyping give us an actionable information that we could do something when knowing if a patient has or not a GBA mutation when we are thinking of a patient as a candidate for [00:13:00] DBS?

[00:13:00] Prof. Enza Maria Valente: Yeah, we've started to believe that GBA genotyping will probably have to enter the routine and diagnostic path in a patient with Parkinson's disease because it's going to impact not only, the choice to perform or not perform DBS, but also it will provide information about potential prognosis.

For instance, we're looking a little bit more in depth into the dysautonomia that seems to be a more relevant feature in GBA patients. And it could be important to see whether these could be better targeted and managed in these patients and obviously also for family reasons as well.

And all the trials that are ongoing that will be starting in the near future. So to know whether a patient carries or doesn't carry a GBA mutation will have a relevance, especially in light of the high frequency of this genetic factor, which obviously is not comparable [00:14:00] to the extremely rare cases patients who carry other monogenic forms of Parkinson's disease, even if those are with higher penetrance, so I would definitely think that these will become more routine. Yes.

[00:14:15] Dr. Michele Matarazzo: Perfect. Well, you've answered already to my next question, but looking forward, what further research is needed in this area in GBA, PD and DBS. What are your plans for the future?

[00:14:27] Prof. Enza Maria Valente: Well we are expanding our cohort both within the Italian Parknet network, and we are collecting in our database a larger number of patients with or without the GBA and DBS. And we're also focusing on GBA patients who did not underwent DBS despite having a similar clinical characteristics in order to address the issue, whether it's GBA mutation or the DBS are more relevant in terms of influencing on the cognitive outcome.

 So that's [00:15:00] clearly a first point is just to collect larger cohorts and main focuses are to better characterize variants and genotype phenotype correlates within different subgroups because we still observe such a wide clinical variability even within GBS even within GBA cases and so it will be important to stratify these patients better, because probably even within the GBA group, we observe different phenotypes and different behaviors that are related to other variants that we still don't know.

There is interesting literature showing that, for instance, the polygenic risk score may influence the clinical outcome in patients carrying the GBA mutations. So also within, for instance, the big effort of the GP2 genetic consortium, which is worldwide large genetic effort to genotype a very large number of patients from different countries and ethnicities, and that will provide an extremely [00:16:00] useful resource to observe the combination of genetic data on large cohorts at a worldwide level and see, for instance, how other genetic factors may impact or influence on the outcome of the GBA mutation in terms of phenotype, in terms of response to treatment.

So this is definitely something we're looking forward to because it will provide exciting exciting data to better understand PD outcome and also we need better biomarkers as well. So we really hope that for instance, a synuclein seed assay in blood will become a reality soon.

We're still struggling with these say in the peripheral blood, but hopefully in a short time this should become a marker and that would probably also help stratifying patients better and so we definitely need a combined approach. When we say personalized medicine, it means that [00:17:00] every patient is different and it's not just the genetics is not just the imaging, but we need to put together a lot of data in order to obtain profiles of each patients and use these profiles to see how they can better respond to a certain treatment or a certain strategy. 

[00:17:18] Dr. Michele Matarazzo: Well, a lot of work to do, right? 

So finally, Micol, what message would you like our listener to take away from your study?

[00:17:25] Dr. Micol Avenali: I think that the main messages is that DBS at the end in this study is a good option for patients with Parkinson's disease. Even with GBA mutations is very important, although to counseling the patients before the surgery, even if they have a mutation. So this could be very useful to explain what will be the benefit of the surgery and possible complications, in this case, cognitive decline.

[00:17:54] Dr. Michele Matarazzo: Thank you. Well Dr. Avenali, Professor Valente, thank you so much for sharing your insight and research [00:18:00] with us today.

[00:18:00] Prof. Enza Maria Valente: Thank you so much. It's been a pleasure.

[00:18:02] Dr. Micol Avenali: Thank you very much for the kind invitations and to be here today with you.

[00:18:07] Dr. Michele Matarazzo: Thank you all for tuning in. To learn more about this study, visit the webpage of the journal and stay tuned for our next episode. Until next time, take care