帕金森病深部脑刺激中的基因检测

欢迎收听MDS播客，这是国际帕金森病与运动障碍学会的官方播客。

And welcome to the MDS Podcast, the official podcast of the International Parkinson and Movement Disorder Society.

我是主编米凯莱·马塔拉佐，今天我们将很高兴推出与学会科学问题委员会合作的特别系列节目。

I am Michele Matarazzo, editor in chief, and today we are excited to launch a special series in collaboration with the scientific issues committee of the society.

该系列内容也将刊登在他们的常规博客上。

This will also be featured on their regular blog.

在本期首播节目中，我们非常荣幸地邀请到以色列耶路撒冷哈达萨医疗中心帕金森病与运动障碍科主任大卫·阿尔卡迪尔医生，以及美国俄亥俄州克利夫兰诊所神经修复中心运动障碍研究员萨尔·阿尼斯医生。

In this inaugural episode, we have the pleasure of speaking with doctor David Arkadir, head of the Parkinson's disease and movement disorders unit at the Hadassah Medical Center in Jerusalem, Israel, and doctor Sar Anis, a movement disorder fellow at the center for Neurological Restoration at Cleveland Clinic in Ohio, The United States Of America.

欢迎两位，感谢你们的参与。

So welcome and thank you both for joining us.

感谢您的邀请。

Thanks for the invitation.

谢谢，很高兴能来到这里。

Thank you, it's great to be here.

今天我们将探讨遗传学和基因检测在帕金森病深部脑刺激治疗中的作用。

Today we'll explore the role of genetics and genetic testing in deep brain stimulation for Parkinson's disease.

这是一个不断发展且对临床实践和患者护理日益重要的领域。

This is an evolving field with increasing relevance for clinical practice and patient care.

本集是在与Jan Paul医生的合作下制作的，他是MDS科学问题委员会的成员，我要感谢他的合作与贡献。

This episode was developed in collaboration with Doctor.

Jan Paul是MDS科学问题委员会的成员，我要感谢他的合作与贡献。

Jan Paul, a member of the scientific issues committee of the MDS, and I want to acknowledge his collaboration and his contribution.

让我们从第一个问题开始。

Let's start with the first question.

基因检测正日益成为我们常规临床实践的一部分，使我们更接近所谓的个性化医疗。

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.

那么，David，为了设定背景，您能否为我们概述一下目前我们对遗传学和基因检测在帕金森病深部脑刺激中的相关性有哪些了解？

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?

是的，我先简单谈谈基因检测。

Yeah, so say a few words about genetic testing generally.

根据最近发表的研究，我们了解到，全球至少有10%的帕金森病患者携带GBA1基因突变，约有3%的患者携带LRRK2基因突变。

So we know by just at least recent studies that were published that up to ten percent of PD population worldwide are positive to mutation in a gene named GBA1 and about up to three percent in a gene named LARC2.

我们还有其他基因，但我们将主要讨论这两个基因。

We have other gene as well, but we'll dedicate most of the talk to those two genes.

在某些人群中，上述比例更高，比如阿什肯纳兹人群。

In some population, the percentages as quoted are higher, like in the Ashkenazi population.

当涉及到DBS或成人先进疗法时，单基因帕金森病患者可能在这些先进疗法的候选人群中占比更高。

And probably when it's regarded to DBS or adult advanced therapy, probably there is over representation of people with monogenic PD that are a candidate for those advanced therapies.

这些基因不仅对DBS至关重要，也对其他先进疗法具有重要意义。

Those genes are highly relevant, not just for DBS, but also for other advanced therapies.

我们还知道，即使不考虑DBS，平均而言——当然不能对个体一概而论——携带GBA1突变的患者预后比未携带突变或携带LARC2突变的患者更差。

We also know that without even when it's not related to DBS, on average, I mean, you can never say about the individual, but on average, so people with a mutation in GBA1 has a worse prognosis than people without mutation, or with mutation in LARC2.

携带GBA1突变的患者更容易出现神经精神问题和认知障碍。

People with GBA1 have more tendency to develop neuropsychiatric issues, cognitive issues.

此外，运动症状可能更严重，抗帕金森药物的需求也更高。

Also the motor disease is probably more aggressive, a increase in the anti PD medication.

我们也知道，短期内，对于所有合适的候选者，DBS都是有效的。

We know also that in the short term, DBS is successful for all good candidates.

我们预期DBS能够改善运动波动，并帮助减少药物使用，特别是当DBS靶向丘脑底核时。

We expect DBS to improve the motor fluctuation and enable us to reduce medication, especially if the DBS is targeted to the septalamic nucleus.

关于不同基因突变的长期DBS效果，我们了解多少？

What do we know about the long term DBS for the different mutation?

我们知道，对于LRRK2突变患者，长期预后可能优于GBA患者；GBA患者更容易更快出现认知问题和轴性症状，这些症状在DBS术后数年对多巴胺和刺激治疗更具抵抗性。

So we know that for LARC2, probably the long term prognosis is better than for GBA patients develop faster cognitive issue and the axial issue, which are dopamine and stimulation resistance, are more aggressive in the years following DBS.

主要的问题是——我认为这也是本播客的核心议题——我们是否应该为此负责，或者DBS-STN是否加速了GBA患者中观察到的认知衰退？

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 observed in GBA?

这仍然是一个悬而未决的问题。

And this is still an impending question.

这实际上是我认为这里最重要的一点，我们需要深入讨论。

Well, that's actually one of the most important points I think here and that we will have to discuss.

让我把这个问题交给Sar来回答。

Let me turn this question to Sar actually.

David已经提到过这一点，重点关注携带GBA1突变的患者。

David was already mentioning this, focusing on patients who are carriers of GBA1 mutation.

目前的证据是什么？

What is the current evidence?

大卫已经提出了一个非常重要的观点，即特别是对于携带这种基因突变的患者群体，可能存在认知方面的风险。

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.

谢谢，米凯莱。

Thank you, Michele.

目前的证据表明，GBA1携带者从DBS中获得的运动益处与非携带者相似，包括运动障碍减少、运动波动减轻以及药物需求降低。

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.

但有一些重要的研究，比如Avenali和Valente一年前发表的研究，以及Gian Paul和Christopher Goats几年前的研究，表明GBA1携带者在DBS术后认知衰退速度更快。

But there are a few important studies like those published by Avenali and Valente a year ago and Gian Paul and Christopher Goats a couple of years ago showing that GBA1 carriers tend to experience faster cognitive decline after DBS.

认知衰退的程度可能取决于GBA1变异的严重程度，例如，轻度或严重的神经病性变异与更大的认知损害相关，而风险变异则相对较轻。

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.

此外，GBA1携带者在DBS术后似乎也更容易出现直立性低血压和精神病性发作。

So GBA1 carriers also seem to have a higher risk of orthostatic hypotension and psychotic episodes after DBS.

这一发现确实引发了对长期认知影响的担忧，正如医生所指出的。

This finding definitely raised concerns about the long term cognitive effects, as Doctor.

阿卡迪乌提到，关于GBA1携带者接受DBS的情况。

Arkadyou said, of DBS in GBA1 carriers.

但目前，我认为我们还无法确定DBS是否真的加速了认知衰退，还是这只是那些本来就更易感人群疾病自然进展的表现。

But at this point I think we cannot say for sure if DBS actually speeds up cognitive decline, or if it's just the natural course of the disease in people who are already more at risk.

之所以如此，是因为缺乏严谨的随机对照试验，以及未接受DBS的患者对照组匹配不佳。

So the reason for that is the lack of methodology, sound randomized controlled trials, and well matched comparison groups of patients who did not get DBS.

很难将手术本身的影响与遗传状况的影响区分开来。

It's hard to separate the effects of the surgery itself from the impact of genetic conditions.

这些观点非常好。

So those are very good points.

大卫，我不知道你是否想补充些什么，但我有个问题想问你：鉴于这些信息，你在临床实践中推荐脑刺激治疗前，是否会常规检测GBA1突变？

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?

目前，我们并不将其作为常规操作。

So currently, we are not doing it as a routine.

首先，正如索尔所说，我们仍然不知道如何应对检测结果，也不清楚如何向患者解释阳性发现。

First, as Saul said, so we still don't know what to do with the answer, how to explain patients about positive finding.

DBS的适应症是运动波动且认知功能相对保留。

The indication for DBS is motor fluctuation with relatively preserved progression.

因此，如果患者符合这些标准，我们仍不确定如何处理GBA1阳性结果。

So if the patient is fulfilling those criteria, we are not sure what to do with a positive GBAI answer.

DBS是否会导致认知功能加速衰退，这个问题仍悬而未决。

The question whether accelerated cognitive impairment can be caused by the DBS is still pending.

有一些不错的研究，但也存在其他相互矛盾的证据。

There are a nice paper, but there's also other contradictory evidence.

因此，我们不会常规安排患者进行GBA基因检测。

So this is why we are not routinely sending patients for GBA testing.

不过，我想就这个总体观点提出三点不同看法。

Still, I would like to say three different comments on this general comment.

首先，如果我让患者接受基因检测并发现其携带LRRK2突变，这在某种程度上令人安心，因为我们知道LRRK2突变患者无论是否接受DBS，长期预后都较好。

So first, if I send a patient to a genetic testing and we find it to be positive for LARC2 mutation, so this is in a way reassuring, because we know that LARC2 better prognosis for the long run with DBS and without pre DBS.

这是其中一点看法。

So this is one of the command.

第二点，我认为在面对边界情况时，GBA仍可纳入我们的决策，比如年龄处于临界值、认知功能处于临界水平的患者，当您不确定是否应推荐手术时，或许可以纳入GBA检测，因为您知道，携带GBA突变的患者无论是否接受DBS都可能恶化，手术风险可能并不值得。

The second, so still I think GBA can be incorporated in our decision when you have borderline cases, like people with a borderline age, people with an individual with borderline cognition, when 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 the risk for the operation is not justified.

第三个评论可能就是我到目前为止所说的内容。

And maybe the third comment is what I said until now.

这涉及到我们的临床实践和研究。

It's regarding our clinical routine, regarding research.

对患者进行检测非常重要，以便积累经验，更好地应对未来播客中的这些问题。

It's important to test patient, to learn, to cognate experience, so we'll be able to address those questions better in future podcasts.

很好。

Great.

实际上，让我们回到不是未来的播客，而是之前的播客内容。

And actually getting back to not the future podcast, to previous podcasts.

Saur之前提到了Avenali及其同事与Danza、Maria Valente发表的论文。

Saur was mentioning before the paper published by Avenali and colleagues and with Danza, Maria Valente.

这篇论文曾在这档播客中介绍过，我邀请所有听众回听那一期节目。

And this was featured on this podcast, so I invite all of the listeners to go back to that episode.

我想这篇论文大约一年前发表在《JNNP》上。

I think it was about a year ago when it was published on the JNNP.

因此，如果你们感兴趣，这个访谈也仍然可以收听。

So that interview is also available in case you're interested.

现在回到访谈内容并继续讨论，有一个提到的点我觉得我们可以多探讨一下，那就是除了是否携带基因突变之外，并非所有突变都相同。

Now going back to the interview and moving forward, 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.

特别是对于GBA1基因，这一点尤其重要。

And specifically for GBA1, this is particularly relevant.

您能否进一步阐述一下，目前是否有相关证据，或者您对GBA1中的轻度突变、风险变异或严重突变有何看法？

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?

也许还可以简单解释一下这些突变类型分别是什么，以及它们对DBS治疗可能有何影响。

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

是的，我觉得这个问题非常好。

Yeah, so I think this is a great question.

我认为这是我们目前最缺乏答案的问题之一。

And I think this is one of the most unanswered questions that we have.

展望未来，我认为研究还应关注这一具体问题，即基因内的不同遗传变异——例如GBA1，但不仅限于此，对吧？

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?

那LRRK2呢？所以这是一个重要问题，但我仍觉得我们目前还处于更好地理解每个基因影响的阶段，然后再深入探讨具体的变异类型。

What about LRRK2 other 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.

例如，那些可能导致戈谢病的轻度和重度变异，对吧？

For example, mild and severe variants, which can cause Gaucher, right?

或者与戈谢病不一定相关、但被发现会增加帕金森病风险的风险变异。

Or versus risk variants, which were found to increase the risk for Parkinson's, but not necessarily related to Gaucher's.

所以问题是，这些不同的变异是否对DBS治疗效果产生不同影响？

So the question is, are those different variants have different effect on DBS outcomes?

正如我提到的，我认为——大卫，请纠正我——目前专门针对特定变异的研究论文并不多。

And as I mentioned, I think David, please correct me, but there are not a lot of papers focusing specifically on specific variants.

但例如，吉安·帕奥曾专门研究过这个问题，并进行了具体分析，确实发现了不同变异之间的差异。

But for example, Gian Pao focused on that and did specific analysis and saw actually differences between different variants.

事实上，我认为这是一个非常重要的问题，因为我们知道，特定的变异可能会影响疾病进程，对吧？

And actually, I think it's a very important question because we know that specific variants might affect the disease, right?

严重的GBA1变异可能导致更严重的疾病和进展。

Severe GBA1 variants might cause a more severe disease and progression.

因此，问题随之而来：DBS是否会使这些患者的情况变得更糟？

So the question arises whether DBS might affect those patients even worse.

大卫，你对此有什么看法？

David, what do you think about that?

是的，我同意。

Yeah, I agree.

我觉得这是一个有趣的问题。

I think it's an interesting question.

我们知道，严重突变的自然病程比GBA中较轻突变的病程更差。

We know that the natural history of severe mutation is worse than those of milder mutation in the GBA.

但也有一些例外，比如E326K突变，这是一种轻度突变，但更与认知问题相关。

Also, is some exception, like the E326K mutation, which is a mild mutation, but is more associated with cognitive issues.

但正如萨罗所说，我认为我们仍处于争论是否应在DBS中考虑GBA的阶段，尚未进入精细调整哪种突变类型与更高认知风险相关的阶段。

But as Saro said, I think we're still in the stage of debating whether GBI 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.

是的，而且情况更复杂了，我很有信心，目前关于DBS在这方面没有任何证据。

Yeah, and even more complicated, and I'm pretty confident there is no evidence about this regarding DBS.

那么不同基因之间的相互作用呢？

What about the interaction between different genes?

比如说LRRK2和GBA，因为我们知道这两者基因之间存在相互作用。

Let's say LRRK2 and GBA, because we know that there is an interaction between these two genes.

是的，这

Yeah, it's

还要更复杂一些，

a bit more and,

这没完没了。

it's endless.

我们必须一个基因一个基因地来，因为Ben想在突变类型之间做区分。

We have to go by a gene before Ben wants to split between mutations.

我其实更想稍后再谈这个问题。

I would actually like to talk about it later on maybe.

好吧，我们现在来谈谈LRRK2。

Okay, well let's talk about LRRK2 a little bit now.

Sar，你觉得LRRK2突变也被研究作为帕金森病DBS疗效的预测因子吗？

Sar, what do you think that LRRK2 mutations, those are also being explored as predictors of DBS outcomes in Parkinson's disease.

你是否想讨论一下目前对LRRK2基因突变如何影响DBS疗效的理解？

Do you want to discuss the current understanding of how mutation in the LRRK2 gene might influence the results of DBS?

当然。

For sure.

我认为，基于当前的证据，包括五六年前提发表在《JAMA》上的一项出色荟萃分析，这个话题比GBA1更容易讨论。

I think that this is maybe easier topic to discuss compared to GVA1 based on current evidence, including a great meta analysis done about five or six years ago, published in JAMA.

还有我们一年前在《PRD》上发表的一项最近的以色列研究，关于LRRK2帕金森病患者。

And even a recent Israeli study that we published a year ago in PRD about LARC2 PD patients.

看起来他们从DBS中获益的程度与特发性帕金森病患者相当。

It seems that they benefit from DBS just as much as those with idiopathic PD.

他们对多巴胺能治疗和DBS的反应都很好，据我们所知，术后认知衰退或精神病的风险并未增加。

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.

当然，这与我们之前提到的GBA1携带者形成对比。

Of course this is in contrast to GBA1 carriers, as we said.

但实际上，一些研究甚至表明，LRRK2帕金森病的进展可能比特发性帕金森病还要缓慢，这意味着DBS的长期效果可能更好。

But in fact some studies even suggest that LRRK2PD may progress slower compared even to idiopathic PD, which could mean even better long term outcomes with DBS.

然而，目前还没有任何随机对照试验直接比较LRRK2携带者与非携带者的DBS疗效。

That said, there haven't been any randomized controlled trials directly comparing DBS outcomes in LRRK2 carriers.

因此，我们仍需更多研究来了解任何基因变异特有的影响。

So we still need more research to understand any variant specific effects.

但根据目前所知，我可以肯定地说，LRRK2帕金森病患者仍然是DBS的强有力候选者。

But based on what we know so far, I can say that LRRK2 PD patients remain strong candidates for DBS.

很好。

Great.

大卫，你对此有什么看法？

And David, what do you think about this?

你同意这一点吗？

Do you agree with this?

是的，我基本同意。

Yeah, I generally agree.

我认为对于LRRK2来说，情况更简单。

I think with the LARC2, it's simpler.

总体而言，这种疾病更为良性。

Overall, the disease is more benign.

所以，如果在患者因运动波动需要手术时进行手术，他们可能有更长的时间从中获益。

So if you operate them at the stage that they need operation because of motor fluctuation, probably they have more years to benefit from the operation.

总体而言，这里那里都有些证据。

Are generally, there are evidences for there, here and there.

XB与Sardot在方法论上并没有严格构建，但可能其益处持续时间更长。

XB with Sardot is nothing methodologically constructed, but that's probably the benefit is lasting for longer.

当你开始与患者沟通时，这让人感到安心。

And then it's assuring when you're starting to talk to.

那么，让我问另一个问题：在为特定患者建议DBS的整个过程中，将基因检测纳入决策时，有哪些伦理和临床挑战？

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 suggesting DBS for a specific patient.

也许还有一些与我们之前讨论的基因相关的内容，比如GBA1和LRRK2。

And maybe if there are some specific things related to those genes we've been talking about more, which are GBA1 and LRRK2.

所以我认为，这一切也涉及伦理层面，对吧？

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

是的，我认为主要的伦理问题是，当我们面对一个问题时，我们并不确定它是否真的存在。

Yeah, I think the main ethical issue is that you don't know if we have a question that it's there on the table.

我们房间里有一头大象，但他们不知道该如何应对。

We have an elephant in the room and they don't have an answer how to refer.

那么，当我们还不确定该做什么时，是否应该建议患者进行基因检测？

So should we refer patients to gene testing when we don't know, not sure yet what to do?

当结果出来后，我们应该与患者分享多少数据？当我们自己都对证据不够了解时，又该怎么做？

With the results, how much data, how much we should share with the patient when we are ourselves or not aware of the evidence?

我认为，这才是主要的问题。

This is, I think, the main issue.

我个人倾向于公开与患者讨论这个问题，让他们知道这个疑问是存在的。

I will say that personally I'm trying to openly discuss patients and to let them know that the question is on the table.

但从伦理上讲，给患者提供所有信息并期望他们对是否接受手术发表意见，却忽视了我们最终必须给出建议的角色，这其实很容易。

But it's also ethically easy to give the patient all the information and to expect him to be opinionated 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.

我们是主治医生。

We are the treating physician.

我们了解现有数据的局限性。

We know the limitation of existing data.

我们了解疾病的自然病程。

We know the natural history of the disease.

当面对患者时，在大多数情况下，我们知道如何判断帕金森病的进展速度。

When you have patients, in most cases, we know we can see how aggressive is PD.

我们可以根据我们的经验和数据，预测未来可能发生的情况。

We can expect what would be happening in the future, so based on our experience and data.

因此，最终我们必须与患者分享我们的个人建议，而当你缺乏足够可靠的数据时，这一点尤其成问题。

So in the end, we have to share with the patient our personal recommendation, and that this is particularly problematic when you don't have enough data to rely on.

所以，当我遇到一位患者，如果他是合适的候选人，并且向我征求意见时，我会告诉他，虽然有一个小注释：关于GBA型帕金森病患者接受DBS后认知加速下降的问题尚存争议，但若他是理想候选人，我仍建议他接受手术。

So when I have a patient, if he's a good candidate, and he asks me to share my opinion, tell him that with this small asterisk that there is a raised question regarding the accelerated cognitive issue following DBS in GBA PD, that my recommendation if it's an ideal candidate to go for it.

但你仍然会向患者说明，文献中可能存在一些提示，认为这可能会加速认知过程，或者

But you will still disclose to the patient that there might be some suggestion in literature that this might accelerate the cognitive process or

是的，我会和患者分享这一点。

Yeah, I share it with the patient.

你分享了，好的。

You share it, okay.

哪些患者想听这些？

Which patient want to hear?

有些患者希望深入讨论，有些患者只是想要一个个人意见。

Some patient to discuss it more, some patient just asking for a personal opinion.

但没错，如果患者已知自己的基因状态，我总会分享这一点。

But yeah, I will always share if the patient is known the genetic status.

正如你所说，如今许多患者都知道自己的基因状态。

And as you said, today many of the patients know their genetic status.

萨德，你的做法也一样吗？

And Saad, do you have the same approach?

是的，我认为这可能是最大的问题，即其中的伦理层面。

Yeah, I think that this is maybe the biggest issue, the ethical component of this.

我完全同意大卫的观点，但我必须补充一点：我觉得问题在于，我们作为医生和运动专家，是否已经做好了准备？

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?

我们是否准备好向携带这些突变的患者传达有关这些基因突变对其预后影响的正确信息？

Are we ready to deliver to the patients that carry those mutations the right message about the impact of these genetic mutations about their outcomes?

我们每个人都有自己的观点，而且我们的观点可能各不相同。

And each one of us has an opinion and maybe our opinions are different.

因此，我认为一个重要环节是教育医疗提供者，以提升伦理水平。

So I think that an important component would be to actually educate providers in order to improve ethics.

当我们传递信息时，说左旋多巴可以改善帕金森病的运动症状，这往往很容易，对吧？

When we deliver a message, sometimes it's easy to say that levodopa improves motor symptoms in Parkinson's, right?

因为有大量证据支持。

Because there's so much evidence.

但在疾病这一重要阶段向患者告知基因检测结果，意义重大。

But informing patients about genetic results at this important stage of disease is huge.

更不用说资源匮乏的人群了，对吧？

And not talking even about underserved populations, right?

他们获得基因检测的机会更少，机会也更少。

That they have less access to genetic testing and less opportunities.

所以我认为讨论伦理问题很重要，对吧？

So I think it's important to discuss ethics, right?

而且重要的是要把这个问题提上议程，以正确的方式教育我们自己和我们的患者。

And it's important to put this on the table and educate ourselves and our patients in the right way.

还有很多工作要做。

So a lot of work to do.

现在谈到这个，展望未来，你们两人认为哪些研究领域最有可能帮助我们理解帕金森病中遗传学与深部脑刺激之间的相互作用？

And now talking 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?

大卫，你也许可以先开始说。

David, you maybe want to start with that.

是的，所以现在我们进行手术的患者通常是认知功能正常、有运动波动的患者。

Yeah, so I would say that now when we operate the patients, it's usually those are patients who are cognitively fine with motor fluctuations.

在大多数情况下，患者的预期寿命可达数十年。

So in the majority of cases, the life expectancy is decades.

因此，他们术后仍能活二十年、三十年，甚至在某些基因突变的情况下活得更久。

So, and we still, they can live twenty, thirty, even in some gene mutation, even more after the procedure.

尽管使用STM DBS已有三十年，且在欧洲有更丰富的持续多巴胺能疗法经验，美国的经验稍少一些，但美国也已有十余年乃至更久的使用经验，我们至今仍不清楚哪种方式——是先进疗法还是保守疗法——能最好地帮助患者长期保持行动能力，更不用说长达数十年的寿命，同时尽可能维持他们的认知功能。

And still, thirty years after using STM DBS, and many years of experience with 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 decades, and to give them the best chance to keep their cognition for as best as they can.

因此，这仍然是一个开放性的问题。

So it's still an open debate.

在使用这些先进疗法多年后，这个问题依然悬而未决。

It's still an open issue after so many years of using those advanced therapies.

而现在，新出现的疗法是左旋多巴/卡比多巴（Sinemet）。

And now with the new guy on the block, which is the first level dopa for Scarbidopa.

因此，这个问题变得更加复杂了。

So this question is even becoming more harder.

因此，我认为作为MDS社群，我们必须建立一条研究方向和协作机制，系统性地收集数据，以回答有关GBA1突变患者和非GBA1突变患者的问题。

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 mutation.

所以这 generally 是一个开放性问题，当涉及到遗传背景时，情况变得更加复杂。

So this is an open question generally, and of course, when you come to a genetic background, so it's become even more complex.

所有这些数据都必须积累起来。

All those data have to be accumulated.

我认为，最终，唯有长期坚持才是唯一的途径。

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

那么，Sar，你怎么看？

And Sar, what do you think?

David 提到，我们必须重新塑造我们对待帕金森病患者先进疗法的整体方式，使其更具个性化，对吧？

So David was mentioning that we have to reshape the whole scenario of how we approach the advanced therapy for Parkinson's disease patients in a more personalized manner, right?

不仅要考虑遗传因素，还要考虑临床状况，以及其他可能相关的生物标志物。

Not only genetics, also the clinical situation, maybe other biomarkers that could be interesting.

那么，你对这一切有什么看法？

So what do you think of all of this?

更具体地说，遗传因素将如何影响这些决策？

And obviously more specifically of how the genetic will impact these decisions?

对，有几点要说。

Right, so a few things to say.

首先，我认为我们需要一些长期的队列研究。

First, I think we need some long term cohort studies.

关于深部脑刺激和基因遗传进行随机对照研究非常困难，但正如大卫所说，我们需要更多多中心研究，追踪携带GBA1、LRRK2等基因的患者。

It's very hard to do a randomized control study regarding DBS and genetics, but we do need more, as David said, multicenter studies tracking patients with GBA1, LARC2, etcetera.

这非常重要，我认为我们正在努力推进这项工作。

So this is very important and I think we're trying to do that.

但我还设想了其他方向。

But I also envision other directions.

我认为，像机器学习这样的AI驱动模型，可以同时分析基因、运动和临床数据。

I think that AI driven models like machine learning approaches, analyzing genetic, but also motor and clinical data together.

正如你所说，米凯莱，也许是生物标志物，对吧？

And as you said, Michele, maybe biomarkers, right?

SCA、α-突触核蛋白、皮肤活检。

SCA, alpha synuclein, skin biopsies.

现在有大量数据正在涌现。

There's so many data right now coming through.

因此，利用人工智能模型来发现我们医生可能忽略的模式，我认为这是未来非常正确的方向，不应仅仅依赖其中某一种方法。

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.

另一个我想到的方向是，我们之前也讨论过，那些携带GBA1和LARC2基因的患者怎么办？

Another direction I thought was, and we talked about it earlier, what about patients that have GBA1 and LARC2?

他们虽然罕见，但确实是患者。

They are rare, but they are patients.

我认为另一个有趣的方向是关注多基因风险评分。

And I think that another interesting direction would be to focus on polygenic risk scores.

因为，大卫，我认识大卫很多年了，我知道他在这方面有丰富的经验。

Because, and David, I know David for years and I know he's saying that he has a lot of experience with those kinds of patients.

他曾一两次告诉我，他有一些携带严重GBA1突变的患者预后良好。

And he told me once or twice that he has some patients with severe GBA1 mutations that did well.

而他也有其他一些预后较差的患者。

And he has other patients who did less well.

所以问题是，我们能否仅仅依赖于这个变异本身？

So the question is, can we rely just on the variant itself?

还是我们应该关注患者的整个情况？

Or should we look at the whole landscape of a patient?

如果我们这样做，就能获取更多信息，或许能更好地指导我们。

And if we'll do that, we could capture more information and maybe it would inform us better.

因此，我认为多基因风险评分是关于DBS和遗传学研究的另一个重要方向。

So I think polygenic risk scores is another important direction for research about DBS and genetics.

所以所有这些显然都非常复杂。

So all of this is obviously very complex.

仅仅关注一个基因，以及该基因或基因突变在DBS本身已经很复杂的情况下所起的作用。

Only looking at one gene and what's the role of that gene or that mutation within a gene where DBS is already complex.

但若再与其他基因混合，考虑不同基因之间的相互作用，并将这一切置于患者的具体情境中——包括年龄、接受的治疗以及众多新兴的生物标志物——这就变得极其复杂。

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.

我真的希望你们两位，作为该领域的活跃研究者，有充足的时间和精力来开展所有这些研究。

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.

而且正如你们所讨论的关于合作，我想你们已经彼此合作了，这绝对是未来的方向，因为现在我们需要收集大量数据，才能最终得到一些答案。

And Maybe as you were discussing about 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.

是的，毫无疑问。

Yes, definitely.

我们才刚刚开始。

We just started.

是的。

Yeah.

非常感谢您，医生。

Thank you very much, Doctor.

阿卡迪尔医生。

Akhadir, Doctor.

阿尼斯。

Anis.

感谢你们两位带来如此富有洞察力的讨论。

Thank you both for this insightful discussion.

我非常喜欢这次交流。

I really enjoyed it very much.

您的专业知识揭示了深部脑刺激和帕金森病先进疗法中这一非常复杂但日益重要的方面。

Your expertise sheds light on the very complex, but increasingly important aspect of DBS and advanced therapy in Parkinson's disease.

对于我们的听众，感谢您收听本期MDS播客的特别节目。

And to our listeners, thank you for tuning in to this special episode of the MDS Podcast.

敬请关注我们与科学问题委员会合作的新系列讨论，再见各位。

Stay tuned for more discussions in our new series in collaboration with the scientific issues committee, and goodbye to everyone.

谢谢。

Thank you.

本播客中参与者表达的观点和意见不一定反映国际帕金森病与运动障碍学会或其附属期刊《Movement Disorders》和《Movement Disorders Clinical Practice》的立场。

The views and opinions expressed by the participants in this podcast do not necessarily reflect those the International Parkinson and Movement Disorder Society or their affiliated journals, Movement Disorders and Movement Disorders Clinical Practice.

参与者的任何利益冲突声明可在MDS网站上的本集描述中找到。

Any disclosures of the participants can be found within the episode description located on the MDS website.