运动障碍的历史：MPTP与帕金森症的故事

欢迎收听MDS播客，这是国际帕金森病与运动障碍学会的播客频道。

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

我是蒂亚戈·奥塔鲁，德国盖廷根大学医学中心的教授。

I'm Tiago Ottarou, a professor at the University Medical Center Gattingen in Germany.

今天，我很荣幸邀请到美国斯坦福大学的神经病学、神经科学和病理学临床教授威廉·朗斯通教授。

Today I have the pleasure to interview Professor William Langston, clinical professor of neurology, neuroscience and pathology from Stanford University in The US.

嗨，比尔。

Hi, Bill.

非常感谢您参加我们的MDS播客。

Thank you so much for joining us on this MDS podcast.

今天我们在这里讨论的是三十多年前的一项历史性发现，它极大地影响了我们对帕金森病的理解与研究。

We are here today to talk about historical discovery more than thirty years ago that had tremendous impact in our understanding and study of Parkinson's disease.

我们非常期待能从您这里亲耳听到这个故事。

And so we are really very excited to hear this story in the first person from you.

那么，您能告诉我们关于MPTP的故事吗？

So can you tell us the story of NPTP?

这在短时间内会很有挑战性。

Well, it's going to be challenging in a short period of time.

这确实是一个真实的医学侦探故事。

It is a true medical detective story.

如果你有兴趣读我的书《罗斯和吸毒者病例》，会很有趣。

It's a lot of fun to read if you ever wanna read my book, The Cases of Rose and Addicts.

但这一切始于一个临床观察，我想强调的是，直到今天，临床观察在医学发现中仍然至关重要。

But it started with a clinical observation, and I like to point out that even to this day, clinical observations are huge in medical discovery.

当你遇到一个不寻常的病例时，永远不要假设你看到的不是新东西。

Never assume, when you see an unusual case, that you are not seeing something new.

要深入追踪，并保持好奇心。

Follow it through and be curious.

在这个案例中，有一位患者来到我所在的瓦利医疗中心，精神科和神经科的医护人员为此发生了争论。

In this case, it was a patient who entered Valley Medical Center where I was attending, and there was an argument between the psychiatry staff and the neurology staff.

神经科的医护人员认为这位患者患有紧张型精神分裂症。

The neurology staff thought this particular patient was catatonic schizophrenic.

精神科医生认为他是神经科问题，于是我被叫去调解。

The psychiatrist thought he was neurologic, and I got called down to mediate.

我花了大约三十秒就弄明白了。

It took me about thirty seconds to figure it out.

这位所谓的紧张性精神分裂症患者，实际上有齿轮样强直，这是帕金森病的典型体征。

This catatonic schizophrenic, quote, had cogwheel rigidity, a classic sign of Parkinson's.

我以前检查过紧张性患者，会感受到明显的抵抗，而不是这种齿轮样表现。

And I'd examined catatonic before you feel an active resistance to them, not this cogwheel.

因此，我们立刻意识到这个惊人的病例属于神经科问题。

So immediately, we knew this amazing case was neurologic.

然后，心脏部分的问题开始了。

Then the heart part started.

为什么？

Why?

过几天再来。

Come over a couple of days.

时间上，它与典型的帕金森病完全无法区分。

Time, it was absolutely indistinguishable for typical PD.

我当时在车站。

I was in the station.

他才43岁，正如我所说，过来几天看看。

It was only 43, and as I said, come on over days.

我们发现他有个女朋友，后来发现她也有同样的症状。

So we found out he had a girlfriend, and later, it turned out she had the same thing.

我们猜测可能是家里一氧化碳中毒之类的原因。

We thought maybe carbon monoxide in the house, that kind of thing.

结果发现这并不是一个病例。

That turned out not to be a case.

然后我们在圣克鲁斯发现了一些病例。

And then we found some cases in Santa Cruz.

那是离我们大约30英里远的一个地方，那里的人也出现了同样的症状。

That's a place about 30 miles from us who also had it.

唯一的共同点是他们都是海洛因滥用者。

The only common link was they were all heroin abusers.

于是，泽诺·蔡斯开始朝这个方向调查。

So Xeno Chase started in that direction.

我们与警方一起进行了突袭行动。

We went out with police raids.

我们收集了不同的样本试图分析这件事，这实际上是一个令人震惊的故事。

We got different samples trying to analyze this thing, and it was quite a harrowing story, actually.

案件的突破发生在我们得知美国国立卫生研究院（NIH）有一名年轻男子自行合成物质的案例时。

The break in the case came when we learned of a case at NIH where a young man had been making his own synthetic.

美国国立卫生研究院的调查人员试图弄清这个案例。

And the investigators at NIH had tried to figure the case out.

他们有样本。

They had samples.

他们已经做了分析。

They'd done analyses.

他们始终没有找到答案。

They they never figured out the answer.

一名犯罪实验室的技术员给了我这份文件，但它已经有大约15年历史了。

And a crime lab technician put me under this paper, but it was about 15 years old.

于是我联系了那个实验室。

So I called that lab.

这已经是经过大量工作之后的事了。

This is after a lot of work.

我联系了那个实验室，说我们掌握了原子序数和研究数据，但不知道背景信息。

I called that lab and said we had the atomic number, study, but we didn't know the context.

但我指出，你们这里有几个代谢物。

But I said, you have several metabolites here.

你们有原始化合物。

You have the original compound.

这些物质中，有哪个导致了这种情况吗？

Did any of them cause this?

他们说，没有。

And they said, no.

我们试过的所有方法都失败了。

Everything we tried failed.

这就是我们放弃的原因。

That's why we gave up.

他们从未找出答案。

They never figured it out.

通过原子序数，我说，最右边的这个化合物，即现在的MPTB，其原子量正好与我们所研究的物质相符。

And using the atomic number, I said, this compound on the far right, the tabline, which is now called MPTB, has the exact atomic weight of what we're looking at.

他说，对了。

He said, bingo.

我找到了。

I've got it.

他说，那是我们唯一没试过的。

Said, that's the only one we didn't try.

天哪。

Oh my god.

我们解开了这个谜团。

We solved the mystery.

是啊。

Yeah.

有趣的是，他们被严重误导了，因为那些其他物质是麻醉品。

Funny too, they were very misled because these other were narcotics.

当你给大鼠注射海洛因这样的麻醉品时，它们会僵住，进入木僵状态。

And when you give a rat a narcotic like heroin, they freeze up and become a catatonic.

所以这看起来就像他们在病人身上看到的情况，于是他们一直追查下去。

So it looked just like what they saw on the patients, and they kept chasing it.

事实证明，如果给大鼠注射鸦片类药物，它会发展出一种戏称为‘鼠木僵症’的现象。

It turns out it's well known if you give an opiate to a rat, it develops what's teasingly called Rathetonia.

他们完全被误导了。

And they totally misled them.

所以我们果断地做了另一次分析，我们终于找到了。

So we rasphatic, did another analysis, we had it.

我们终于弄清楚了真相。

We finally had what it was.

这改变了历史。

And that changed history.

它提供了一个真实的帕金森病模型。

It lived a diverse true model of Parkinson's.

我一直被教导说，我们没有一个好的帕金森病模型。

We didn't I was always taught, we don't have a good model of Parkinson's.

事实上，它是一种在环境中与百草枯相似的简单化合物。

In fact, it's a very simple compound similar to Paraquat in the environment.

这会是一种环境毒素吗？

Could it be an environmental toxin?

它成为研究黑质细胞退化的一个绝佳工具。

And it was a magnificent tool to study nigra cell degeneration.

这种化合物能直接通过血脑屏障，进入黑质并将其摧毁。

This compound goes right in blood through the blood brain barrier, right to the nygre and knocks it out.

这是一种了不起的化合物，被用于研究帕金森病的各个方面。

Amazing compound that's been used for all types of studies of all aspects of PD.

这一切都始于那位患有紧张性木僵的患者。

It all started with that one patient who either was having catatonic fuselage.

是的。

Yeah.

这真的令人惊叹且难以置信。

That's really amazing and unbelievable.

所以出于好奇，那些受影响的人是同时使用这些物质的吗？还是这只是巧合？

So just out of curiosity, were those people that were affected, were they using together or was this just a coincidence as well?

他们并没有同时使用。

They were not using together.

我们真正找到关键线索的方式是，我有一位住在圣克鲁兹的同事。

The way we really found a key in the story was, I had a fellow who lived in Santa Cruz.

我们有两个病例。

We had two cases.

也许这只是环境中的原因。

Maybe it's just in the environment.

我的意思是，家里有什么东西，因为他们住在一起。

I mean, in the home, something in the home because they live together.

他正在和来自更南边的沃森维尔的一位神经科医生共进晚餐。

He was having dinner with a neurologist from Watsonville, that's further south.

这位神经科医生与这一切毫无关联，他说：我遇到了两个奇怪的病例，是两个兄弟，他们突然像盐柱一样僵住了。

This neurologist, totally unattached to any of this, said, I had these two weird cases, their two brothers, and they just froze up like a pillar of salt.

做我们这些病例的那位同事说：天哪，听起来一模一样。

And my fellow who did our cases said, oh my god, it sounds the same.

我们下去对他们进行了检查。

We got down to examine them.

这是唯一与恐惧和虐待有关的联系。

It was the only connection with terror and abuse.

如果他们全都待在一起，我们仍然会去寻找环境中的某种因素，就像我之前说的，比如一氧化碳，或者吃了什么东西。

If they'd all been together, we would have still been searching for something in the environment, as I said, like carbon monoxide or something like that or eating something.

关键是这些病例之间完全没有任何关联。

It's the fact those cases were totally unassociated.

我们找到了这个共同的联系。

We had that common link.

因此，在这项调查中，我迈出了关键的一步。

And so we had, I was one step in this investigation.

是的。

Yeah.

就像你所说的，MPTP会导致帕金森综合征，其症状与帕金森病相似，但显然不是帕金森病。

And like you said, so MPTP causes Parkinsonism, which manifests with similar symptoms to Parkinson's, but it's not of course Parkinson's disease.

这一点非常重要，因为人们有时会误以为，当他们在小鼠或实验室中使用MPTP时，是在模拟帕金森病。

So this is an important concept to leave here because people sometimes think that when they use MPTP in mice or in the lab, they are modeling Parkinson's.

他们实际上是在模拟帕金森综合征。

They are modeling Parkinsonism.

我认为这是一个重要的概念。

I think this is an important concept.

出于好奇，这些患者对左旋多巴和其他典型的帕金森病疗法有反应吗？还是存在差异？

And out of curiosity, did those patients respond to levodopa and to other typical PD therapies or are there differences?

在这一层面上，你们也观察到任何差异了吗？

Did you see any differences at that level as well?

这是个很好的问题。

That's a great question.

我们对此有过一些争论。

We had some debate over that.

从临床表现上看，它与帕金森病完全相同。

Clinically, it looked identical to Parkinson's.

患者严重残疾，甚至难以进食。

The patients were severely disabled, even had trouble eating.

实际上，我不确定他们能否存活很久。

And actually, I'm not sure they would have survived very long.

因此，基于这一点，看起来像是帕金森病，患者需要治疗，我们给了他药物，三小时后，他们就能正常行走。

So based on that, it looked like Parkinson's, patients need it, we gave him Three hours later, they were up walking around in normal.

我不知道你有没有看过电影《苏醒》，我觉得这里演病人的演员就是。

I don't know if you've ever seen the movie Awakenings, but I think, here's the actor that played the patient.

他们展示说，他们给他用了左旋多巴，而他之前一直处于类似木僵的状态，我想已经有三十年了。

They showed that that they gave him levodopa in the awake and she'd been in, like, catatonic, I think, thirty years.

当他们回来时，床已经空了。

And when they came back, the bed was empty.

他正在外面走动。

And he was out walking around.

而视频评论员说：‘这太荒谬了。’

And the video critic said, oh, that's ridiculous.

这不过是好莱坞的夸张罢了。

That's just Hollywood.

不对。

Nope.

当然。

Absolutely.

那是真实情况。

That was reality.

是的。

Yeah.

有效果。

It worked.

有效果。

It worked.

这种帕金森状态对左旋多巴有反应，但随着时间推移会改善吗？还是说患者遭受的是永久性损伤？

And this Parkinsonian state, so it responded to levodopa, but did it improve with time or did it stay was it a permanent damage that the patients had?

这是个非常好的问题。

That's a really good question.

他们出现了很多副作用，包括幻觉，但并非所有人都有。

They had a lot of side effects, including hallucinations, and not all of them.

我真的很想研究一个长期接受大量强效药物的大脑。

And I really wanted a brain that's been getting a lot of major league drugs.

就像帕金森病一样，左旋多巴也会引发幻觉。

Just like Parkinson's, levodopa can induce hallucinations.

而且他们都很年轻，其中几个人出现了严重的不自主运动。

And they were young, and several of them developed very severe dyskinesias.

在我看来，这是典型的年轻患者表现。

And that's, in my opinion, typical young.

他们出现症状的速度更快、时间更早。

They get much quicker and earlier.

有一位患者在三周内就出现了不自主运动，这在典型的帕金森病中是不常见的。

One one patient got dyskinesias within three weeks, which you don't usually think of with typical PD.

事实上，《苏醒》中也描绘过这种情况。

Actually, that was depicted in the Awakenings too.

因此，存在许多并发症。

So there are lots of complications.

最后一点，我知道他说的是开玩笑的。

And the last thing is I I can tell it was tongue and cheek.

医学的目标通常是帮助患者恢复到能够重返正常生活状态。

A goal in medicine is usually to get a person back where they can resume their normal life.

那个车站的家伙是个毒贩和瘾君子。

That per station was a drug dealer and junkie.

而我们实际上让他重新去卖毒品了。

And we actually returned him to selling drugs.

是的。

Yeah.

我认为他之后再也没有用过那些药。

I don't think he used them again.

天啊，他惹上了各种麻烦。

And boy, he got in all kinds of trouble.

我觉得有一次，某个帮派盯上他了。

And I think at one point, some gang picked him out.

所以他的正常生活被毁了，但这并不一定是一件好事。

So he was wrecked his normal life, but that wasn't necessarily a good thing.

其他人活得更久，但同样面临副作用、药物使用不当等问题。

Others lived longer but again, had problems with side effects, not using their drugs correctly, etcetera.

有一位患者被刊登在《新英格兰医学杂志》上。

One patient was in a New England Journal.

我们送一位患者去瑞典接受胚胎细胞移植。

Sent one patient to Sweden for a embryonic cell transplant.

这在一段时间内确实帮到了她，但最终还是无效了。

That did help her a while, but eventually, it didn't.

她后来严重残疾，几年后去世了。

She wound up terribly disabled and eventually died years later.

我现在正在整理这篇报告。

It's really I'm writing this up right now.

另一方面，有一位患者，我们不得不把他从监狱里接出来，还有两名州警在病房里陪着，我们为他进行了深部脑刺激。

On the other hand, one patient who we had to get him out of jail and two state troopers in the hospital room with him, we did deep brain stimulation.

他表现得很好。

He did great.

他大约六个月前因肝癌去世了。

He just died of liver cancer about six months ago.

所以这是黑质的一个病灶，而DBS正是针对这一点。

So it's a single nigra lesion, and that's what DBS does.

这在细胞移植和DBS之间形成了一个非常有趣的对比，目前他们正在重新尝试细胞移植。

And it's a real interesting comparison between cell transplantation, which they're trying again right now.

我们三十年前尝试过，但失败了。

We've tried thirty years ago and failed.

DBS是一对一的治疗，但有一次它失败了，没有奏效。

And DBS, it's a one on one, but one that failed, it didn't work.

而DBS和另一个病例也接受了DBS治疗。

And the DBS and the other one had DBS.

他基本上是依靠辅助生活来维持的。

Pretty much he had assisted living with it.

他过着相当不错的生活。

He loved a pretty good life.

所以，我认为这是一个非常有趣的对比。

So, I think it's a very interesting comparison.

我们将把这三个病例整理成文。

We're going to write the three cases up.

是的，当然。

Yeah, absolutely.

这些病人中有谁做过尸检吗？

And did any of those people come to autopsy?

你知道他们的大脑是否显示出路易小体病理吗？

And do you know if their brains showed Lewy body pathology?

这是一个价值百万美元的问题。

That is a million dollar question.

答案是否定的。

And the answer is no.

所以，没有病理表现？

So, no pathology?

没有病理表现。

No pathology.

在猴子身上，我们看到了一些类似路易小体的东西，并且在副丘脑核中发现了它。

In monkeys, we saw something that looked a little like Lewy bodies, and we saw it in the paramegular nucleus.

结果发现，阿尔茨海默病和帕金森病经常同时出现。

And it turns out, very often you see concurrent Alzheimer's and Parkinson's.

在这些情况下，那个区域有很多路易小体。

And in those cases, lots of Lewy bodies in that area.

但我们从未能令人信服地证明我们发现了路易小体。

But we were never able to convincingly prove we had Lewy bodies.

我认为我们有几个病例接近了，但始终没能确认。

I think that we had a few cases where it was close, but never could.

它更像帕金，帕金在大多数情况下几乎就是一个谜。

It's come more like Parkin Parkin, is pretty much in some most cases just an enigma.

是的。

Yeah.

所以这表明，当损伤如此剧烈时，可能没有足够的时间形成通常需要数十年才能成熟的路易小体。

So it suggests that maybe when it's such an aggressive damage, maybe there's not enough time to form the mature Lewy bodies that would normally take decades to to form.

是的。

Yeah.

除了那位接受DBS治疗并活得足够久的人之外。

And then except for the one who had DBS lived long enough.

这是个非常好的观点。

That's a very good point.

不幸的是，他去世了。

Unfortunately, he died.

我当时不在城里。

I was out of town.

我们没能及时赶过去，但那本会是一个极其难得的病例。

And we were not able to get to bring, but that would have been an incredible case to him then.

不。

No.

这非常有趣。

So this is very interesting.

当然，人们必须去读你的书，才能了解所有那些细节，我相信这些细节会让它更加有趣。

Think, of course, people have to go and read your book to understand all the little details that I'm sure would make it even more interesting.

为了节省我们听众的时间，关于这一历史发现，你还能分享其他有趣的事实或轶事吗？

In the interest of time for our listeners, are there any other interesting facts, anecdotes that you could share related to this historical finding?

太多了。

There are just so many.

我想，这里有个轶事：我们有一位病人有严重的震颤，去了某所顶尖大学医院。

I guess, here's an anecdote: one of our patients had severe tremor and went to a major university hospital.

他们把他拍成了苯中毒病例，一种红色震颤。

And they filmed him as a case of phenosizing toxicity, a red tremor.

我确实拿到了那段视频。

And I got actually got the video.

它在他们的教学图书馆里。

It was in their teaching library.

他们说这是一个酚噻嗪中毒的病例。

And they said this is a case of phenosizing toxicity.

你可以看到它会导致完全型帕金森病，出现严重震颤，作为教学案例。

You can see it causes full bone Parkinson's, severe tremor, as a teaching case.

唯一的问题是，他从未接触过酚噻嗪类药物。

The only problem was he'd never been exposed to phenothiazemesis.

就在桥的右侧。

Right of the bridge.

我想，如今这种倾向依然存在。

And I guess this is a tendency this day.

你总觉得所有出现过的东西都已经被见过。

You think everything that's ever out there you've has been seen.

所以我们总是想把事情硬塞进错误的洞里。

So we always wanna ratchet it into the wrong size hole.

在这种情况下，核苷酸是有毒的。

In this case, nucleoside is being toxic.

不是烦人。

Not annoying.

他们可能已经得到了它。

They might have gotten it.

他们把它推进去了，那是在我的任何病例之前。

And they pushed it in, and that was before any of my cases.

直到今天，他还在教学实验室被出院了。

And he got discharged in teaching lab to this day.

非常有趣。

Very interesting.

但我认为在这个层面上有很多教训可以吸取。

But I think there's a lot of lessons at that level to be learned.

是的。

Yeah.

比尔，非常感谢你。

Bill, thank you so much.

听你简要讲述这个完整故事的过程非常愉快。

It has been very nice listening to this brief and short version of the full story.

但我希望这足以吸引我们的听众去阅读你关于这一发现的著作。

But I hope this is enough to entice our listeners to go and read your book about this finding.

非常感谢你参与本期播客。

So thank you so much for participating in the podcast.

我的荣幸。

My pleasure.

我们此前采访了威廉·朗斯顿教授，他讲述了上世纪八十年代MPTP作为导致帕金森综合征的毒素的历史性发现。

So we've interviewed Professor William Langston on the historical discovery of MPTP as a toxin causing Parkinsonism back in the early eighties.

感谢大家的收听，欢迎关注我们的下一期播客。

We thank you all for listening, I invite you to join us in our upcoming podcasts.

本播客中参与者所表达的观点和意见不一定反映国际帕金森与运动障碍学会及其附属期刊《运动障碍》和《运动障碍临床实践》的立场。

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

与会者的任何利益冲突声明均可在MDS网站上的该集描述中找到。

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