本集简介
双语字幕
仅展示文本字幕，不包含中文音频；想边听边看，请使用 Bayt 播客 App。
大家好。
Hey, everyone.
欢迎收听《Drive》播客。
Welcome to the Drive podcast.
我是你们的主持人，彼得·阿蒂亚。
I'm your host, Peter Attia.
这个播客、我的网站以及我的每周通讯，都致力于将长寿科学转化为每个人都能理解的内容。
This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone.
我们的目标是提供健康与福祉领域最优质的内容，为此我们组建了一支优秀的分析团队来实现这一目标。
Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen.
对我来说，不依赖付费广告来提供所有这些内容至关重要。
It is extremely important to me to provide all of this content without relying on paid ads.
为此，我们的工作完全依赖于我们的会员支持。
To do this, our work is made entirely possible by our members.
作为回报，我们为会员提供独家内容和额外福利，这些是免费用户无法获得的。
And in return, we offer exclusive member only content and benefits above and beyond what is available for free.
如果你想将你对这一领域的认知提升到一个新的层次，我们的目标是确保会员获得远超订阅费用的回报。
If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of the subscription.
如果你想了解更多关于我们高级会员权益的信息，请访问 peteratiamd.com/subscribe。
If you want to learn more about the benefits of our premium membership, head over to peteratiamd.com/ subscribe.
本周的嘉宾是丽莎·莫斯科尼。
My guest this week is Lisa Mosconi.
丽莎是一位神经科学家、神经影像专家，同时也是威尔康奈尔医学院女性大脑倡议的主任，她领导着关于性别差异——尤其是更年期和荷尔蒙转变——如何影响大脑衰老和阿尔茨海默病风险的研究。
Lisa is a neuroscientist, neuroimager and the director of the Women's Brain Initiative at Weill Cornell Medicine where she leads research on how sex differences, especially menopause and hormonal transitions, shape brain aging and Alzheimer's risk.
她还是一位神经科学教授，是脑成像技术的先驱，这些技术能够在阿尔茨海默病出现症状前数十年就对其进行映射。
She's also a professor of neuroscience and a pioneer in brain imaging approaches that map Alzheimer's disease decades before symptoms appear.
在本集中，我们探讨了为什么阿尔茨海默病对女性的影响更为显著，以及为什么女性比男性更长的寿命并不能完全解释这种两倍的差异。
In this episode we talk about why Alzheimer's disproportionately affects women and why women's increased lifespan over men does not fully explain that 2x difference.
讨论阿尔茨海默病实际上是女性在中年时期就开始的疾病，其发展远早于症状的出现。
Talk about the idea that Alzheimer's disease is actually a midlife disease for women beginning long before symptoms.
以及更年期本质上是一场大脑事件，这一转变过程中大脑的能量、结构和免疫信号会发生怎样的变化。
And how menopause is fundamentally a brain event and what happens to brain energy, structure and immune signaling during that transition.
我们讨论了先进成像技术如何揭示阿尔茨海默病的临床前期表现。
We talk about what advanced imaging reveals about pre clinical Alzheimer's disease.
我们谈到了丽莎在雌激素脑受体成像方面的工作。
We talk about Lisa's work in imaging estrogen brain receptors.
我们讨论了ApoE4基因以及其他遗传风险因素，以及为何这些因素似乎对女性的影响大于男性。
We talk about ApoE4, specifically other genetic risks and why they impact women seemingly more than men.
我们探讨了更年期激素治疗的细微证据，包括其风险、益处、时机、制剂类型，以及为何妇女健康倡议（WHI）引发了数十年的困惑。
Some of the nuanced evidence around menopausal hormonal therapy risks, benefits, timing, formulations and why the WHI caused decades of confusion.
我们谈到了丽莎的新倡议——CARE计划，这是一个全球性努力，目标是在2050年前将女性患阿尔茨海默病的风险降低一半，并介绍了一些基于证据的实用策略，以在中年过渡期支持大脑健康，涵盖生活方式、睡眠、新陈代谢、情绪，以及药物（如GLP-1激动剂和SERMs）的重要作用。
Talk about Lisa's new initiative called the CARE Initiative, a global effort to cut women's Alzheimer's risk in half by 2,050, along with some practical evidence based strategies for supporting brain health throughout midlife transitions including lifestyle, sleep, metabolism, mood, and the involving role of medications including GLP-one agonists and SERMs.
那么，不浪费时间了，请享受我与丽莎·莫斯科尼的对话。
So without further delay, please enjoy my conversation with Lisa Mosconi.
丽莎，非常感谢你今天抽出时间来和我交流。
Lisa, thank you so much for coming out to spend time with me today.
谢谢你邀请我。
Thank you for having me.
这实际上是一个很棒的播客，因为它结合了我们在本播客中已经深入探讨过的两个话题。
This is actually a wonderful podcast because it combines two topics that we have spent a lot of time on in this podcast.
这两个话题也是我们在临床实践中花费大量时间关注的。
It's two topics that we spend a lot of time on in our clinical practice.
但据我回忆，这可能是我第一次在这里将它们交汇起来讨论。
But it is probably, at least to my recollection, the first time I've brought them into an intersection here.
其中一个话题是所有与女性健康相关的内容。
So one of them is all things that pertain to women's health.
特别是从绝经前期、围绝经期到绝经后期的过渡过程。
In particular, the transition through pre, peri and post menopause.
这依然是一个我们非常重视并持有鲜明观点的话题。
Again, this is a topic we care deeply about and have very strong points of view on.
而另一个话题当然是大脑健康，我相信没有一位听众会不理解退行性脑疾病对寿命的缩短作用，但或许更重要的是，它们如何严重压缩了健康寿命。
And then the other of course is brain health, which I don't think there's a single person listening to this podcast who doesn't appreciate both the role of the dementing diseases in how they truncate lifespan, but perhaps much more importantly how they truncate health span.
我今天想和你交谈的原因，是因为你正处在女性健康与大脑健康这两个领域的交汇点上，你提出的问题正是针对女性与大脑健康的具体关联。
And the reason I wanted to talk with you today was because you sit at the intersection of these two, which is you're asking the questions as they pertain specifically to women and brain health.
所以我想先简单聊聊你的背景。
So I just want to maybe start with a bit of your background.
你能告诉我，你是怎么把这定为你的研究方向的吗？
So tell me how you came to find this as your focus.
这对我来说非常个人化。
It's quite personal for me.
我出生并成长于意大利的佛罗伦萨。
So I was born and raised in Florence in Italy.
顺便说一句，佛罗伦萨真的是地球上最棒的地方之一。
Which by the way, just wanna say, literally one of the greatest places on this planet.
真的很美。
It's really pretty.
直到我搬离之后，我才真正意识到佛罗伦萨有多美。
I never appreciated how pretty Florence is until I moved.
我为此感到非常自豪。
I'm quite proud.
每次我回去，都会觉得，哦，这里真不错。
Whenever I go back, it's like, oh, this is really nice.
正如你可能知道的，或者人们可能知道的，在意大利，家庭成员通常住在一起。
As you may know, as people may know, in Italy, families really live together.
我出生并成长于意大利的佛罗伦萨。
So I was born and raised in Florence.
我的父母住在佛罗伦萨。
My parents live in Florence.
我的祖父母也住在佛罗伦萨。
My grandparents were in Florence.
我的父母都是核物理学家。
And my parents are nuclear physicists, both of them.
我来自一个有趣的家庭，家里一半的人都拥有博士学位，通常是物理学方向的。
I come from an interesting family where half of the family has a PhD, usually in physics.
另一半则在军队服役。
The other half is in the army.
所以我们这些人都是非常有纪律的科学家。
So we're very disciplined scientists, some of us.
我成长于这样一个环境，一切都围绕着物理、生物、学习和研究。
And I grew up in this environment where everything was about physics and biology and studying and learning.
于是我决定将这些知识应用到医学中。
And I decided to apply that knowledge to medicine.
所以我拥有一个哲学博士
So I have a Ph.
学位。
D.
专业是神经科学和核医学，这是放射学的一个分支。
In neuroscience and nuclear medicine, which is a branch of radiology.
我经常做脑部扫描。
I do a lot of brain scans.
大约在我开始研究神经科学，特别是记忆和语言的时候。
Around the time that I started studying neuroscience and specifically memory and language.
但我对记忆功能和认知能力非常感兴趣。
But I was very interested in memory functionalities and cognition.
和我父母住同一层楼的祖母，开始表现出认知衰退的迹象。
My grandmother, who lived on the same landing as me and my parents, she started showing signs of cognitive decline.
我的祖母是家里的顶梁柱。
My grandmother was the rock of the family.
她是一位坚强、极其聪慧的女性，经历过二战，并独自抚养了一大家子。
She was this really strong, extremely intelligent woman who went through World War II, and she raised the family.
我的祖父曾是战俘，服役于军队。
My grandfather was a prisoner of war, being in the army.
很长一段时间里，没有任何事情击垮她的精神，直到她开始失去记忆，失去沟通能力，失去照顾我们的能力，甚至记不得如何做饭。
For a long time, nothing broke her spirit until she started losing her memory, until she started losing the ability to communicate, until she started losing the ability of taking care of us, where she could not remember how to cook.
这彻底击垮了祖母，也击垮了我们，最终被诊断为阿尔茨海默病。
And that really broke my grandmother and broke us and led to a diagnosis of Alzheimer's disease over time.
更可怕的是，我祖母是四个兄弟姐妹中的一个，三个姐妹和一个弟弟。
And what was even scarier is that my grandmother was one of four siblings, three sisters, and one brother.
三位姐妹都患上了阿尔茨海默病并因此去世，而兄弟却没有患病，得以幸免，尽管他们都活到了相同的年龄。
All three sisters developed Alzheimer's disease and passed away from it, whereas the brother did not and was spared, even though they all lived to the same age.
那是什么年龄？
Which was what age?
我祖母去世时已经八十多岁了。
My grandmother passed when she was in her late 80s.
她患病多久了？
And how long did she suffer with the disease?
什么时候开始的？
When did it start?
至少十年。
At least a decade.
非常微妙。
It was very subtle.
阿尔茨海默病通常是以渐进的方式开始的。
Very often Alzheimer's disease starts in a gradual way.
起初，她有一些轻微的认知障碍，但几乎能掩饰过去。
At first, there's some mild cognitive impairment, which she was able to almost masquerade.
她有一些策略来找到答案，继续日常活动，却从不告诉我们她其实很吃力。
She had strategies to find the answer, keep going about today without really telling us that she was having a hard time.
但后来情况就变得很明显了。
But then it became quite evident.
最后，病情变得非常严重，因为她其他方面都很健康。
And in the end, it was very severe because she was healthy otherwise.
所以她的身体是健康的，但大脑却不行了。
So her body was healthy, but her mind was not.
所以三位姐妹基本上都在八十多岁时因病去世，发病时间在七十多岁末，我提到这一点只是为了说明，这是非常典型的病程。
So all three sisters basically succumbed to this in their late eighties, having the onset in their late seventies, which again, I bring that up only to say this is a very typical trajectory.
这非常典型。
It's very typical.
不幸的是，这相当常见。
Unfortunately, it is quite typical.
这可能超出了你的研究范围，因为我知道你不是临床医生，但鉴于你有如此个人的经历，人们经常问我一个问题：患者在什么时候会意识到正在发生的事情，从而产生极大的痛苦？而在什么时候，认知障碍已经严重到他们不再感到痛苦，只有我们周围的人在承受痛苦？
This might be a question beyond your research because I know you're not a clinician, but given that you had such a personal experience, one of the things people often ask me is, at what point do patients become aware of what's happening such that it creates enormous distress for them versus when is the cognitive impairment so severe that they are no longer suffering and it's only those of us around them who are suffering.
但我们可以从中获得一些安慰，因为患者本身已经不再受苦了。
But we could potentially take some solace in the fact that they are no longer suffering.
根据你的经验，你对此有什么看法吗？
Do you have a sense of that from your experience?
是的。
Yes.
有相关研究显示，随着我们诊断阿尔茨海默病的能力不断提升——不再仅仅依赖临床工具，而是结合脑部成像和血液中的生物标志物等生物学指标——我们现在能够较早地判断一个人是否面临阿尔茨海默病的风险，或是否出现相关警示信号。
There's research in this showing that we're now able, now that we're getting better at diagnosing Alzheimer's disease, not just using clinical tools, but using biological markers like brain imaging and biological fluids in blood.
然后，我们就可以将这些检测结果与患者的自我描述进行关联。
Now, we can tell when a person is at risk for Alzheimer's or is showing red flags for Alzheimer's fairly early on, and then it's possible to correlate that with what the patient is telling you.
因为几十年来我们一直依赖的那些认知测试，用于诊断阿尔茨海默病的，都相当
Because the tests, the cognitive tests that we've been basing the Alzheimer's diagnosis on for decades are quite
滞后。
Quite late.
它们有点滞后。
They're a little bit late.
它们对疾病最早期的表现不够敏感，而这些表现通常是主观的。
They're not quite sensitive to the earliest possible manifestations of the disease, which are usually subjective.
所以我们现在了解到，存在一个前临床阶段，此时疾病已经在进展。
So what we're learning now is that there's a phase that is a preclinical phase where the disease is underway.
你可以在大脑或生物体液中观察到蛋白质和病变。
You can see the proteins and the lesions either in the brain or in biological fluids.
但客观上，还没有出现认知障碍。
But objectively, there is no impairment.
在这一阶段，认知测试中没有任何缺陷。
There is no deficit at that point on cognitive testing.
许多患者会告诉你，他们感觉不一样了。
Many patients would tell you that they don't feel the same.
人们认为，他们意识到某些变化正在发生。
There's this idea that they are aware that something is changing.
他们的表现不再和以前一样了。
That their performance is not the same.
即使只是几年前，他们的表现也不如从前了。
That they're not performing as well as they used to even just a few years prior.
很难说这仅仅是衰老，还是更严重的问题。
And it's very hard to say, is it just aging, or is it something more severe?
现在我们在这方面做得越来越好，但看起来阿尔茨海默病的临床前期可以持续数十年。
And now we're getting better at doing that, but it looks like the preclinical phase of Alzheimer's disease can last decades.
疾病已经开始，大脑中出现负面变化，这些变化缓慢但持续地最终超过大脑的代偿能力。
Where the disease is underway, it starts with negative changes in the brain that very slowly but surely eventually exceed the brain's ability to compensate.
但这需要很长时间。
But it takes a long time.
大脑是一个极其有韧性的器官。
The brain is an extremely resilient organ.
不幸的是，许多患者正处于这种灰色地带，可以说，他们知道有些不对劲。
And unfortunately, many patients are in this gray area, if you will, where they know that something is amiss.
但当他们前来接受神经学评估时，一切看起来都正常。
But when they come for a neurological evaluation, everything is fine.
当他们去看神经心理医生时，测试结果会根据年龄和教育水平与常模进行对比。
When they go to see a neuropsychologist, they test with the normative value by age and education.
因此，如果我们无法诊断出他们实际上正在走向阿尔茨海默病，就很难提供咨询和制定治疗方案。
So it's really hard to provide counsel and to offer a treatment plan if we are not able to diagnose the fact that they are, in fact, on the path towards Alzheimer's disease.
这个过程可能持续数十年。
That could last decades.
它可能持续非常、非常长的时间，直到认知缺陷严重到足以做出客观诊断。
It could last a really, really long time until the deficits are such that there is an objective diagnosis.
通常，患者会在多年里经历不适、抑郁和焦虑，直到痴呆变得严重，开始忘记自己是谁，或忘记自己有家人。
And usually patients do experience discomfort and depression and anxiety for years until dementia is severe enough that they start forgetting who they are, Or they start forgetting that they have a family perhaps.
于是他们开始忘记自己为什么在这里。
So they start forgetting why they are where they are.
因此，不幸的是，这是一种令人心碎的疾病。
So unfortunately, it's a heartbreaking disorder.
丽莎，你刚才以阿尔茨海默病为例所描述的内容，在其他类型的痴呆症中，比如路易体痴呆、额颞叶痴呆或血管性痴呆，有多少是相似的？
Lisa, how much of what you just described through the lens of Alzheimer's disease specifically is comparable in other forms of dementia, such as Lewy body dementia or frontotemporal dementia or vascular dementia?
我的意思是，也许为了观众能更好地理解，我们可以把这些都放在一个整体背景下说明。
I mean, maybe just for the audience, we can put these all in context.
阿尔茨海默病是最常见的痴呆类型，但它远非痴呆的唯一病因。
Alzheimer's disease is the most common form of dementia but it is far from the only cause of dementia.
所以你是否愿意从其他类型痴呆的角度来说明一下，不仅包括它们的患病率，还有你刚才提到的发病和表现上的细微差异？
So do you want to maybe put it in the context of these others, both in terms of maybe some of the prevalence of these but also any of the subtle differences in what you just said as far as onset and presentation?
是的。
Yes.
痴呆是一个总称，涵盖多种不同疾病，这些疾病通常根据病理特征来分类，也就是每种疾病最显著的病变类型。
So dementia is an umbrella term that includes different disorders that are typically categorized in terms of pathology, which is the kind of lesion that every disorder expresses most abundantly.
同时也根据临床症状，有时还包括发病年龄来区分。
And also in terms of clinical symptoms and sometimes age of onset.
大多数人对阿尔茨海默病比较熟悉，通常会误以为阿尔茨海默病和痴呆是同一回事。
Now, most people are familiar with Alzheimer's disease, and they usually think that Alzheimer's and dementia may be the same thing.
这是一个常见的误解。
It's a common misconception.
阿尔茨海默病是最常见的痴呆类型，约占所有痴呆病例的百分之七十。
Alzheimer's is the most common form of dementia, accounting for about seventy percent of all dementia cases.
现在还有其他类型的痴呆。
There are other types of dementia now.
我们越来越多地听到额颞叶痴呆，比如布鲁斯·威利斯不幸被诊断出患有这种病。
We hear more and more about frontotemporal dementia, for instance, because Bruce Willis, unfortunately, has been diagnosed with that.
在这种情况下，临床表现略有不同。
In that case, the presentation is a little bit different.
当我们进行脑部扫描时，实际上可以根据大脑变化的模式来判断患者是患有额颞叶痴呆还是阿尔茨海默病。
When we do brain scans, actually, we can tell whether a patient has frontotemporal dementia or Alzheimer's disease based on the pattern of changes in the brain.
额颞叶痴呆通常在较早的年龄发病，主要与失语症相关，即语言表达能力受损。
Frontotemporal dementia tends to occur a little bit earlier in life, and predominantly is associated with aphasia, which is disturbed language production.
而阿尔茨海默病则更多地影响记忆功能。
Whereas Alzheimer's, it's more about memory function.
更多是关于忘记事情。
It's more about forgetting things.
然而，归根结底，当各种类型的痴呆发展到严重阶段时，症状上会有大量重叠。
However, at the end of the day, once the dementia, the different types of dementia are quite severe, there is a lot of overlap in terms of symptoms that may occur.
病理机制是不同的。
The pathology, the pathophysiology is different.
但晚期的症状往往会出现重叠。
But the symptoms at the end tend to overlap.
因此，做出准确的鉴别诊断相当困难。
So it's quite difficult to do a good differential diagnosis.
路易体痴呆是另一种痴呆类型，由α-突触核蛋白的突变引起。
Lewy body dementia is another form of dementia that is due to mutation in the alpha synuclein protein.
这与阿尔茨海默病略有不同，阿尔茨海默病的主要问题是淀粉样蛋白β的异常产生，形成聚集的斑块，以及神经元内的神经纤维缠结。
So it's a little bit different from Alzheimer's, where the main problem is an amyloid beta, a fibrillar amyloid beta production in lesions that aggregate into plaques, and also neurofibrillary tangles inside neurons.
因此，每种痴呆都有略微不同的生物学基础。
So each one in this dementia has a slightly different biological substrate.
血管性痴呆也非常常见，并且与其他类型的痴呆症状有很大程度的重叠。
Vascular dementia is also very common and tends to overlap with the other types of dementia.
事实上，我们经常提到混合性痴呆。
In fact, very often we talk about mixed dementia.
对于患者来说，仅仅患有阿尔茨海默病而没有任何血管损伤的情况非常罕见。
It's quite rare for a patient to only have Alzheimer's, for instance, and not some vascular damage.
患者仅仅患有阿尔茨海默病而不伴有任何路易体痴呆特征的情况也很少见。
It's rare for a patient to have only Alzheimer's disease and not also some features of Lewy body dementia.
在很多年里，诊断完全依赖临床表现。
And for many, many years, the diagnosis was purely clinical.
那时的诊断有点滞后。
It was a little bit late.
你必须有非常明确的症状，才能被诊断为阿尔茨海默病、路易体痴呆或额颞叶痴呆。
You needed to have very clear cut symptoms in order to be diagnosed as Alzheimer's or Lewy body or frontotemporal dementia.
现在我们有了生物标志物，诊断越来越准确，也越来越早。
Now that we have access to biological markers, we're getting better and better, and the diagnosis has been done earlier and earlier.
因此，这有望为每种类型的痴呆症带来更好的治疗途径，并开发出能够实现这一目标的药物。
So that is hopefully leading to better therapeutic routes for each type of dementia and development of pharmaceuticals that are able to.
目前，我们正试图逆转阿尔茨海默病所造成的损伤，至少在结果上是如此。
Right now, we're trying to reverse the damage that, at least in Alzheimer's, makes results.
我认为，乐观地说，我们正在努力阻止病情进展。
I think optimistically, we might say we're trying to halt progress.
是的。
Yes.
我们正试图摆脱试图逆转痴呆症或严重病变的努力。
We're trying to move away from trying to reverse the dementia or very severe lesions.
我们正试图回溯到更早的时间。
We're trying to move back in time.
我们希望在人们仍相对健康时就介入，此时延缓症状发作甚至预防大脑病变积累的可能性最大，也是切实可行的。
We're trying to catch people when they are still relatively healthy and the potential for delaying the onset of the symptoms or even preventing, hopefully, the accumulation of the lesions in the brain is greatest, is feasible.
因此，我们正致力于与相对年轻的人群合作。
So we're trying to work with people who are fairly young.
这在阿尔茨海默病领域是非常新的。
And that is very new in the field of Alzheimer's.
当我搬到纽约时，我已经在研究阿尔茨海默病的预防，看看能做些什么。
When I moved to New York, I was already looking at Alzheimer's prevention, what could be done.
那是二十年前的事了。
That was twenty years ago.
我当时在纽约大学医学院工作，我的导师是蒙特·德莱昂博士。
And I was working at NYU, New York University, the School of Medicine with my mentor back then, Doctor.
蒙特·德莱昂，他是阿尔茨海默病预防领域的真正先驱。
Monet de Leon, who's really a pioneer in the field of Alzheimer's prevention.
他的团队是全球极少数研究65岁以下人群的团队之一。
And his team was one of the very few teams in the world to work with individuals who were younger than 65.
因为其他人都在研究65岁及以上的群体。
Because everybody else was looking at those who were 65 and older.
他说：不，我们需要更早开始。
He was like, No, we need to start earlier than that.
你提到的这种重叠现象非常有意思。
The point you make about the overlap is really interesting.
这意味着，如果你分别查看每种类型的患病率，总和不会达到百分之百。
It means that if you look at the prevalence of each type, it will not total one hundred percent.
所以你说过，百分之七十的痴呆症病例都带有阿尔茨海默病的成分。
So you said seventy percent of dementia will have an Alzheimer's component.
关于额颞叶痴呆、路易体痴呆和血管性痴呆的总体患病率，大概分别是多少呢？
What are the approximate numbers of frontotemporal, Lewy body and vascular in terms of just aggregate presence?
这很有趣。
It's interesting.
我认为要给出确切的数字很难，尤其是血管性痴呆，因为它总是与其他类型混合在一起。
I think it's difficult to really come up with specific numbers, especially for vascular dementia, because it's always kind of intermixed.
额颞叶痴呆通常大约占20%，但情况也类似，这取决于具体情况。
DuoBody is usually around maybe 20% frontotemporal, but it lies the same, but it depends.
我觉得我们其实很难给出明确的说法。
I don't know that we can really say.
是的。
Yeah.
今天我们将会大量讨论阿尔茨海默病，我们知道阿尔茨海默病在女性中发病率更高。
We're going talk a lot about Alzheimer's disease today and we know that Alzheimer's disease occurs disproportionately in women.
大约是二比一。
It's about two to one.
其他类型的痴呆症是否也 disproportionately 发生在女性身上？
Do any of the other forms of dementia disproportionately occur in women?
没有。
No.
这实际上在我们刚开始研究女性性别与阿尔茨海默病关联时，让我们感到非常有趣。
And that's actually something that was very interesting to us when we started looking at the association between female sex and Alzheimer's disease.
因为当我刚开始研究这个问题时，那是很久以前了，我会问自己：这只是我家族的情况吗？
Because when I started looking into this, this was a while ago, I would ask the question, is it just my family?
还是说我们有必要从中学习更大的教训？
Or is there a bigger lesson that we need to learn?
答案是，自20世纪90年代以来，我们就知道，在衰老之后，女性身份是患阿尔茨海默病最强的危险因素。
And the answer was that we've known since the 1990s that after aging, after getting older itself, being a woman is the strongest risk factor for developing Alzheimer's.
但当我问：我们能做点什么吗？
But when I asked, can we do something about it?
答案大多是：关键在于寿命。
The answer was mostly, well, the point is longevity.
这仅仅是衰老。
It's just aging.
意思是女性比男性活得更久，而阿尔茨海默病是一种老年疾病。
The idea is that women live longer than men, and Alzheimer's is a disease of old age.
所以最终，不幸的是，患阿尔茨海默病的女性比男性更多。
So at the end of the day, unfortunately, more women than men have Alzheimer's disease.
但有两点在某种程度上与这一说法相矛盾。
But there are two things that contradict in part this statement.
显然，衰老是很重要的。
Clearly aging is important.
是的
Yeah.
第一个因素，顺便说一下，只是一个简单的精算分析。
The first one by the way is just a simple actuarial analysis.
十年前我就自己做过一次，随手算了一下，因为那是最初的猜测。
I did this myself ten years ago, back of the envelope, because that was the first guess.
我第一次思考这个问题可能是在2015年，当时很自然的想法是，女性平均寿命比男性长两到三年，这应该就能解释了。
The first time I thought about that question was maybe in 2015 and the obvious answer was, well, women on average live two and a half to three years longer, that must account for it.
但如果你真的去查看像CDC死亡率表这样最基本的数据，并按五年区间细分，你就无法用这短短的年龄差来解释患病率两倍于男性的差距。
But if you actually go through even something as rudimentary as the CDC mortality tables and slice them by five year increments, you can't explain the increased prevalence by a factor of two to one on that delta in age.
但我相信你对为什么这不是主要原因有更精妙的解释。
But I'm sure you have a much more elegant explanation for why this was not the case.
显然，我想到的一点是，寿命差距并没有达到十年。
One thing that came to mind obviously was that the difference in the longevity gap was not ten years.
没那么大，只有几年而已。
It wasn't that wide, was just a few years.
例如，在英格兰，性别差距大约为两年，但阿尔茨海默病和痴呆症这一整个类别是女性死亡的首要原因，而不是男性。
And for instance, in England, the gap is about two years, but Alzheimer's disease and dementia, the whole category is the number one cause of death for women and not for men.
但另一个问题是，如果仅仅是衰老导致的，那么女性患其他与年龄相关的疾病和神经退行性疾病的比例应该高于男性，但实际上并非如此。
But then the other point is that if it was just aging, then women would have a higher prevalence of other age related disorders and neurodegenerative neurodegenerative disorders relative to men, only they do not.
对。
Right.
癌症和心血管疾病也与年龄相关。
Cancer and cardiovascular disease are also age related.
但即使在痴呆症内部，血管性痴呆的男女比例是五五开。
But even within the dementias, right, for vascular dementia is fiftyfifty.
帕金森病伴痴呆更为常见，是的。
Parkinson's disease with dementia is more prevalent Yes.
额颞叶痴呆似乎在男性中更为常见。
In Frontotemporal dementia seems to be more prevalent in men.
路易体痴呆的男女比例大约是五五开。
And Lewy body dementia is about fiftyfifty.
所以，这显然不是一个合理的方式或理由来忽视一个重要的问题。
So that just doesn't seem to be a good way or good reason to dismiss an important question.
我们能否说，当今科学界已经摒弃了这种借口，并完全接受了女性在生物学上存在某种差异，导致了这种巨大差异这一事实？
Is it safe to say the scientific community today has stopped with that sort of excuse and we've now fully accepted the fact that there is something biologically different about women that is leading to this enormous mismatch?
我真希望我们能说他们已经通过了这一点。
I wish we could say they would have passed it.
真的吗？
Really?
是的。
Yes.
是的。
Yes.
在我的领域，这仍然是一个非常活跃的争论话题。
It's still a subject of very active debate in my field.
抱歉，我只是想确认一下，我们是在争论为什么会发生这种情况，还是在争论年龄是导致这一现象的原因？
Sorry, just to make sure I understand, we're debating why it's happening or we're debating that age is the reason that it's happening?
我们在讨论后者。
We're debating The latter.
是的。
That Yes.
我们仍然认为，生存和寿命可能是导致更高患病率的原因。
We're still thinking that survival and longevity is something that may be driving the higher prevalence.
支持这一观点的论据实际上并不差。
And the argument for this is actually not a bad argument.
他们说，患病率是通过横断面观察的。
They say prevalence is something that you look at cross sectionally.
对。
Yes.
那发病率呢？
But what about the incidence?
它是什么时候发生的？
When does it come on?
是的。
Yes.
问题是，如果患病率更高但发病率没有增加，那可能是衰老造成的。
And the question is, if prevalence is higher but incidence is not, then it could be aging.
可能是年龄因素。
It could be age.
没错。
That's right.
所以问题在于，女性患阿尔茨海默病的比率是否高于男性？
So the question is, do women develop Alzheimer's at higher rates than men?
我来给听众解释一下这是什么意思。
And I'll just explain to the listener what that means.
你和我都清楚，发病率是指在特定时间段内新发病例的数量。
You and I obviously understand that incidence is the number of cases that occur over a given period of time.
所以你可能会说，这种癌症的发病率是每年每10万人中有多少病例。
So you might say the incidence of this cancer is this many cases per 100,000 people per year.
正如你所说，患病率是指在任何时间点上患有该疾病的人数的横断面累积总数。
Prevalence, as you stated, is the cross sectional cumulative number of people at any point in time that have the given condition.
因此，根据你的观点，如果每个时间点的发病率相同，但随着时间推移患病率持续上升，那么你可能需要思考一个问题：是不是女性死于这种疾病的比例降低了，从而导致病例累积？
And so to your point, if the incidence is identical at every section in time, but the prevalence keeps getting larger as time goes on, then you might have to ask the question, are fewer women dying of the disease and therefore accumulating cases?
是的。
Yeah.
我认为，由于阿尔茨海默病的诊断标准发生了变化，我们目前很难根据现有研究得出准确的发病率估计；现在我们比过去更早地发现了更多患者。
And I think it's been very difficult to get a good estimate of incidence with the studies that we have because the diagnosis of Alzheimer's disease has changed And over we're catching more people now even earlier than we did in the past.
因此，越来越多的研究表明，女性的发病率也更高，尤其是在低至中等社会经济地位的国家。
So there are more and more studies showing that the incidence is also higher among women, especially in countries with low to middle socioeconomical status.
从数学角度思考这个问题的另一种方式是：正如你所说，发病率非常复杂，因为诊断本身就很复杂，或许更容易通过观察死亡率并统计死亡率差异来分析。
Another way to think about this mathematically would be because, as you said, incidence is very complicated because the diagnosis is so complicated, it might be easier to look at mortality and tally up the mortality differences.
因为如果你真的想反向验证这个假设——如果你认为发病率过高，那么你应该看到男性在与女性相同疾病阶段的死亡率要高得多。
Because if you really think that you would reverse test this hypothesis, if you think incidence is too high, you should see men dying at a much higher rate at a comparable stage of disease to women.
换句话说，如果男女患病率相同，女性应该比男性更长寿，但显然这并不成立，不过这确实是一种从反面检验该假设的方法。
In other words, the women should be outliving the men with Alzheimer's disease if they're all getting it at the same rate, which I don't think is the case of course, but that would be a way to test that hypothesis in the negative.
是的，有可能。
Yes, that could be.
事实上，在一些国家，阿尔茨海默病是65岁以上女性的首要死因。
In fact, in some countries, Alzheimer's disease is actually the number one cause of death for women 65.
这令人震惊。
That's staggering.
疾病，没错。
Disease, yes.
哪些国家？
What countries?
欧洲国家以及美国的一些地区。
European countries and also in some parts of The United States.
因此，相关数据正在陆续公布，因为许多科学家对‘寿命差异’是唯一解释这一差距的说法感到困惑。
So the data is just coming out because many scientists are, in a way, puzzled that longevity has been the only explanation for the disparity.
我们现在正以新的方式审视风险，这些方法更能公正地回应我们过去无法充分探讨的问题，尤其是通过观察生物标志物。
And we're now looking at risk in ways that they think are doing more justice to the question that we could do before, especially by looking at biological markers.
因为我们可以看到这一点，这正是我大量研究的内容：当我们进行脑部成像或分析中年时期的其他生物流体时，我们会比较一组年龄在45到65岁之间的男性和女性，这些参与者都具有阿尔茨海默病的家族史，或者携带APOE4基因型。
Because we can see that and this is a lot of my research when we do brain imaging or we look at other biofluids in midlife and we compare let's say that we have a population of men and women who are like 45 to 65, and all these participants, all these people have a family history of Alzheimer's or perhaps the APOE4 genotype.
因此，从技术上讲，他们的阿尔茨海默病风险高于普通人，也就是那些没有这些风险因素的人。
So they are technically at higher risk for Alzheimer's than the average person, than people who do not have these risk factors.
如果你观察男性和女性的脑部扫描结果——至少在我的研究中，这一点已被许多其他科学家和研究团队重复验证——女性在中年时期表现出的阿尔茨海默病预警信号往往比同龄男性更多。
If you look at the brain scans of men and women, at least in my work, but it's been replicated many other scientists and other teams, the women tend to show more red flags for Alzheimer's disease in midlife as compared to men at the same age.
这一现象非常一致。
And this is quite consistent.
我们还发现，大脑中病变的进展速度在女性中更快。
And we've also seen the progression of lesions in the brain tend to be faster in women.
因此，当比较具有相同症状和相同痴呆严重程度的男性和女性时，女性的大脑实际上承载着更多的病理变化。
So then when you compare men and women who have the same symptoms and the same level of dementia severity, the women's brains actually harbor more pathology.
所以，似乎发生的情况是：我们比男性更早开始在中年时期出现阿尔茨海默病的病变和大脑病理变化。
So what seems to happen is that we start developing the lesions of Alzheimer's, the pathology in the brain earlier on than men starting in midlife.
我们与之共存的时间更长，但我们的代偿能力更强，因为目前用于诊断阿尔茨海默病的测试主要依赖于言语记忆等指标，而女性在这些方面略占优势。
And we live longer with it, but we're able to compensate more in that the tests that we use to diagnose Alzheimer's are heavily reliant on things like verbal memory, which women have a little bit of an advantage in.
因此，早期诊断女性的阿尔茨海默病更加困难。
And so it's more difficult to diagnose Alzheimer's in women early.
因为她们在你们用来检测的指标上具有更高的认知储备。
Because they have a higher cognitive reserve in the metric you're using to test.
是的。
Yes.
所以某种程度上，女性在掩盖大脑中存在阿尔茨海默病的事实，但并不是真的表现得更好。
So in a way, women are masking the fact that there is Alzheimer's in their brains, but not necessarily over performing.
但她们是从更高的储备水平开始的。
But starting at a higher reserve.
是的。
Yes.
从更高的水平开始。
Starting at a higher level.
因此，我们的想法是，女性会更长时间地与阿尔茨海默病共存，这可能导致未来女性阿尔茨海默病患者数量更多。
So the idea is that we live with Alzheimer's longer, and that may lead to a higher number of Alzheimer's patients among women down the line.
这彻底改变了关于女性大脑健康和阿尔茨海默病风险的整个问题。
So that really changed the whole question about women's brain health and Alzheimer's risk.
因为我和其他人所展示的是，阿尔茨海默病并不是一种老年病。
Because what we and others have shown is that Alzheimer's is not a disease of old age.
而是一种中年期疾病，其症状在老年时才显现。
It's a disease of midlife with symptoms that start in old age.
阿尔茨海默病在中年时期就开始在大脑中出现负面变化，随后才导致痴呆的症状和临床诊断。
Alzheimer's starts in midlife with negative changes in the brain and then later on lead to the symptoms and the clinical diagnosis of dementia.
但这改变了问题的方向，对吧？
But then that changes the question, right?
因为如果阿尔茨海默病不是老年病，而是中年期疾病，而女性从中年开始患阿尔茨海默病的风险更高、长期风险更大，那么我认为，我们真正应该问的问题是：中年时期，女性身上发生了什么，而男性却没有，这可能解释了为什么女性日后患阿尔茨海默病的风险更高？
Because if Alzheimer's is not a disease of old age, but it's a disease of midlife, and women have a higher risk of Alzheimer's disease, a higher long life, long term risk of Alzheimer's disease as compared to men starting in midlife, then the question that we should be asking, I believe, is well, what happens to women and not to men in midlife that could then potentially explain the higher risk of Alzheimer's down the line?
是的，我刚把这一点记下来。
Yeah, I just wrote that down.
我觉得这是个非常深刻的见解，丽莎。
I think that's such a profound statement, Lisa.
这让我想起我曾在播客中多次引用的一位嘉宾的话，虽然那是在谈论完全不同的事情——骨质疏松。
It actually reminds me of a statement I've made many times on the podcast quoting one of our guests about something totally different, which is osteoporosis.
那位嘉宾说：你看，骨质疏松其实是一种儿童期的疾病。
The guest said that, Look, osteoporosis is a childhood disease.
但它并不会在儿童时期表现出来。
It just doesn't manifest in childhood.
但对于女性来说，到18或19岁时，骨骼密度就已经达到了遗传所能达到的极限。
But you reach your genetic ceiling of your bone density by the time, in the case of a woman, by the time she's 18 or 19 years old.
所以，如果一个女性在18、19岁之前未能通过足够的骨骼刺激和相关因素来建立强健的骨骼，她的风险就已经开始了，尽管这种疾病要到60岁才会显现。
So if a woman isn't able to create enough deformation in her bones and all of the things that lead to strong bones by the time she's 18, 19, her risk has already started, even though that disease won't manifest until she's 60.
我认为你的例子虽然更令人不安，但表述得非常到位。
And I think your example is frankly even more terrifying, but it's well stated.
那么，我们来谈谈一些相关的理论吧。
So, let's talk a little bit about some of the theories for this.
我认为你和我都非常一致地认为，仅靠年龄本身无法解释这一现象，即使它在一定程度上有所影响。
I think you and I are in pretty strong agreement that age alone cannot explain this even if it partially contributes to it.
年龄一定会有某种滞后效应。
There must be some tail effect of age.
好吧，我们就接受这一点。
Well, let's accept that.
如果任何人认真思考这个问题超过两分钟，第一个浮现在脑海中的想法可能是男女之间的根本差异：男性在整个生命过程中雄激素水平会缓慢下降，但永远不会遭遇雄激素的突然剥夺。
The first idea that I think would pop into anybody's head if they're thinking about this for more than two minutes is a fundamental difference between men and women is that men have a very gradual loss of androgens throughout their life But they're never shocked with androgen deprivation.
而女性则在你提到的这个时期，会突然且剧烈地丧失雄激素。
Whereas women have a sudden and shocking loss of androgens at about the time you're talking about.
在她们生命的中期，她们会失去性激素。
In the middle of their life, they will lose their sex hormones.
当然，问题是，这是否起到了作用？
Of course, the question is, does that play a role?
那么，这个观点在其中处于什么位置？还有哪些其他观点可以解释这一现象？
So where does that idea fit into this and what other ideas fit into it that could explain this?
同样，这在我的领域内是一个非常活跃的争论话题，甚至到了人们几乎觉得必须站队的地步。
Again, this is a subject of very active debate in my field, to the point that people almost feel like they have to take sides.
这非常有趣。
It's very interesting.
在这个时候做这项工作很有趣。
It's an interesting time to be doing this work.
所以我认为一个很好的回答方式是，比如进行脑成像研究，这正是我们一直在做的。
So I think a good way to answer is by, for instance, doing brain imaging, which is what we have been doing.
早在2017年，我们就发表了第一项研究，想到这一点真是令人惊讶。
And back in 2017, we published the first study, which is bizarre to think about it.
那是2017年。
It was 2017.
但那是第一项展示女性绝经前后大脑变化的研究。
But it was the first study showing the brains of women before and after menopause.
在那之前，我们所有的研究都是在绝经后进行的，把绝经更像是一种结果来看待。
Everything we had until up until that point was done after menopause, looking at menopause more like an outcome.
而我们关注的是绝经过渡期发生了什么，这可以说是神经活动最活跃的阶段。
Whereas we were looking at what happens during the transition to menopause, which is the most neurologically active phase, if you will.
所以在第一项研究中，我们有三组女性：月经不规律的绝经前女性、月经周期规律的围绝经期女性，以及年龄不超过65岁的绝经后女性。
And so we had in the first study, we had three groups of women: premenopausal with irregular menstrual cycle perimenopausal with regular menstrual cycles, and postmenopausal up to age 65.
也就是说，一年以上没有月经了。
So no more menstrual cycles for over a year.
这种情况下没有使用激素替代疗法吗？
No hormone replacement therapy in that case?
没有，没有使用激素替代疗法。
No, no hormone replacement therapy.
我们还设置了年龄匹配的男性组，因为绝经前女性通常比绝经后女性更年轻。
And then we had age matched men because premenopausal women tend to be younger than the postmenopausal ones.
我们发现，在绝经前阶段，即月经周期规律时，女性大脑与男性大脑之间几乎没有差异。
And what we found was that before menopause, at the premenopausal stage, regular menstrual cycles, there were barely no differences between women's brains and men's brains.
抱歉，丽莎，你们在这项研究中使用的是哪种扫描方式？
And sorry, Lisa, what type of scan are you using for this?
我们进行了多种脑部扫描。
So we are doing different brain scans.
我们使用MRI来观察脑容量以及脑部病变的存在。
We use MRI to look at brain volume, to look at presence of lesions in the brain.
让我们说得非常专业一些，因为我觉得这真的很重要。
Let's be very technical because I think this really matters.
所以今天我们会讨论很多不同类型的扫描，但作为接受过放射学训练的人，我通常会用一种简化的方式向我的病人和这个播客的听众解释。
So we're going to talk about lots of different types of scans today, but the way I typically try to explain this to my patients and to the listeners of this podcast, oversimplification as someone who's trained in a radiographic field.
我总是希望病人能理解成像技术与功能技术之间的区别。
I always want patients to understand the difference between imaging modalities and functional modalities.
所以，当你看像MRI这样的检查时，你是为了获得解剖结构的分辨率。
So, when you look at a test like an MRI, you are doing it for anatomical resolution.
而且，你可以选择如何进行这种检查。
And again, you can choose how you do that.
你可以选择T1还是T2，FLAIR还是其他序列。
You can T1 versus T2, this flare versus that.
你可以突出显示白质或灰质。
You can highlight white matter versus gray matter.
你可以突出显示血管系统。
You can highlight the vascular system.
但你关注的是解剖结构的分辨率。
But you're looking for anatomic resolution.
相反，如果你做像FDG-PET扫描这样的检查，你并不是在看解剖信息。
Conversely, if you do something like an FDG PET scan, you're not looking at anatomic information.
你是在看功能信息。
You're looking at functional information.
你想了解在FDG-PET的情况下，细胞的代谢活跃程度。
You want to understand how metabolically active, in the case of FGG PET, the cells are.
CT扫描通常更偏向解剖结构等。
CT scans tend to be much more anatomic, etcetera.
你同意这种看待它们的方式吗？
Would you agree with that way to think about them?
你如何看待可用于诊断的各类影像学检查组合？
And how do you think of the suite of different radiographic studies that can be used?
是的。
Yes.
我认为最重要的是你所测量的内容。
I think what's most important is what you're measuring.
你可以使用不同的工具来测量不同的东西。
You can use different tools to measure different things.
一个很好的定义标准是：你是在寻找结构信息、功能信息、生化信息还是病理信息。
And the really good definition is whether you're looking for structure information, for functional information, for biochemical or pathological information.
在磁共振成像扫描中，你当然可以观察大脑的解剖结构，也可以观察体积变化。
With MRI scans, what you can do is look at the anatomy of the brain for sure, is to look at volumetrics.
你希望确保大脑的某些区域神经元密集且健康。
You want to make sure that some parts of your brain are really nice and dense with neurons.
而如果我们发现萎缩的迹象，这可能是未来痴呆症的风险因素。
Whereas if we find signs of atrophy, that could be a risk factor for future dementia.
比如，我们总是关注大脑的一个区域——内侧颞叶，它由一些相对原始的结构组成，这些结构在记忆功能和情绪调节中起着重要作用。
Like there's one part of the brain that we always look at is the medial temporal lobe, which is a combination of structures that are quite primitive, if you will, and that are highly involved in memory function and also emotional regulation.
展开剩余字幕（还有 480 条）
特别是有一个结构，海马体，它被认为是阿尔茨海默病风险的生物标志物。
And there's one structure in particular, the hippocampus, which is considered a biomarker for Alzheimer's risk.
因为海马体，你希望它尽可能大。
Because the hippocampus, you really want it to be as big as possible.
你希望它的体积足够大且健康。
You want the volume to be really nice and large.
但当我们发现海马体及其下方的旁海马回体积缩小和结构变薄时，这就是阿尔茨海默病的风险因素。
But when we find reductions in volume and thinning of the structure of the hippocampus and the parahippocampal gyrus, which is right below, that is a risk factor for Alzheimer's.
这并不意味着你患有阿尔茨海默病。
It doesn't mean you have Alzheimer's.
这意味着这是一个潜在的阿尔茨海默病风险预警信号。
It means that that is a red flag for potential Alzheimer's risk down the line.
就像你提到的，这被称为T1磁共振成像。
And then like you mentioned, this is called a T1 MRI.
我们通常也用它来进行体积测量，以确保没有脑肿瘤，也没有明显的血管性损伤或中风。
We usually use it for volumetrics also to make sure that there are no brain tumors, that there are no obvious vascular damage strokes.
所以这是一个很好的初步指标。
So that's a good first line.
这是一个良好的基线。
It's a good first baseline.
但我们通常还会进行T2和FLAIR扫描，这些扫描能提供其他重要参数的额外信息，比如大脑中的胶质增生，虽然这并不特异，但它是白质完整性受损的迹象。
But we also do usually T2 and FLAIR scans that give you additional information on other parameters that are important, like if you have gliosis in your brain, which is a bit nonspecific, but it is a sign of white matter integrity damage.
这就像大脑中出现的一些小点，通常随着年龄增长而出现，但也可能是炎症或血管损伤的迹象。
It's like little punctuations in the brain that tend to emerge with aging but could also be a sign of inflammation, of vascular insults.
因此，监测这一点很重要。
So it's good to monitor that.
我们可以观察大脑的血管系统。
We can look at the vascular system in the brain.
我还喜欢做的一件事是，我们在所有生物标志物检测中都会使用经过一些改良的MRI。
What I also like to do, and we have it in all our biomarker panels, is that we use MRI with some modifications.
因此，我们可以进行DTI，即扩散张量成像，通过它可以看到大脑的结构连接性，以及连接不同神经元的所有不同纤维。
So we can do DTI, diffusion tensor imaging, where you can see the structural connectivity of your brain, all the different fibers that connect the different neurons.
你可以从这些图像中提取大量信息。
And you can extract a lot of information from those images.
然后我们还使用一种经过修改的MRI技术，通过动脉自旋标记（ASL）来观察血流，这种方法完全无创且非常快速。
And then we also use a modified version of an MRI to look at blood flow with ASL, arterial spin labeling, which is completely noninvasive and is also really quick.
但它有助于判断大脑在任何给定时间是否获得了足够的血液供应。
But it is helpful to look at whether the brain receives enough blood flow at any given time.
然后我们使用波谱分析。
And then we use spectroscopy.
我们进行三维磷-31磁共振波谱分析，以观察大脑中的ATP生成情况。
We do 3D1P, phosphorus thirty one magnetic resonance spectroscopy, to look at ATP production in the brain.
到目前为止，这是唯一的技术，尽管还有一种基于PET的潜在方法正在建立中。
So far, it's the only technique, except there's one potential with PET that's still being established.
但这项技术可以很好地反映磷酸肌酸与ATP生成的比例，我们发现这可能是大脑压力的一个潜在生物标志物，几乎相当于大脑处于能量损伤或危机状态时的信号，表明神经元正承受代谢压力。
But this technique can give you a good read on the ratio of phosphocreatine to ATP production, which we find to also be a potential biomarker for brain stress, almost, when the brain is in a state of energetic damage or crisis that could signify that the neurons are under metabolic stress.
所以我们也会做这项检查。
So we do that too.
这都是MRI。
And this is all MRI.
所以我们可以在一小时内完成所有检查。
So we can do everything in less than an hour.
你能在一次扫描的多个序列中获得所有这些信息吗？
And you will get all that information on multiple sequences of one scan?
是的，我们可以完成所有检查。
Yes, We can do everything.
不过，这些是不同的扫描序列。
Well, it's different scans.
对。
Yeah.
我的意思是，让患者在一次检查时间内完成不同的序列。
I mean, run the patient through different sequences, but under one table time.
是的。
Yes.
一次床时间。
One table time.
我们需要为这个波谱扫描更换线圈。
We do need to switch the coil for this spectroscopy scan.
所以我们只把你推出扫描仪一分钟。
So we bring you out to the scanner for just a minute.
我们更换线圈然后继续。
We switch the coils and go
那个扫描需要多少个线圈？
How many coils do you need for that scan?
至少需要36个，但我认为可能更多。
At least 36, but I think more potentially.
你会从氢切换到磷，但那只是技术人员的操作。
You switch from the hydrogen to the phosphorus, but that's just something the technician does.
在大脑以外的部位做这个，你会因为运动而遇到很大困难。
This is something you would have a really hard time doing outside of the brain because of motion.
是的。
Yes.
哦，是的。
Oh, yes.
大脑的一个优势是你可以把头部固定住，是的。
One advantage of the brain is you lock that head in place Yes.
而且它位于磁体下方，距离很近。
And it's a short distance under the magnet.
是的。
Yes.
所以这些图像非常清晰。
So those are really good images.
此外，我们还进行正电子发射断层扫描（PET）。
And then we also do positron emission tomography or PET scans.
我们使用FTG，就像你提到的，用于观察大脑的代谢活动。
We use FTG, like you mentioned, that looks at metabolic activity in the brain.
我们还使用另一种示踪剂。
And we also use another tracer.
它被称为C-11 PIB，即匹兹堡化合物B，可以显示大脑中的阿尔茨海默病斑块。
It's called c eleven PIB, Pittsburgh Compound B, which shows Alzheimer's plaques in the brain.
这是否就是我们通常所说的淀粉样蛋白PET？
Is that what we would colloquially refer to as an amyloid PET?
是的。
Yes.
这是淀粉样蛋白示踪剂，只是它被标记为碳-11，这意味着你可以立即连续进行FDG和PIB扫描。
It's the amyloid It's just the tracer is then carbonated, has a C11, which means that you can do the FDG and the PIB right away back to back.
你不需要
You don't have to
不需要
don't have to
让患者第二天再回来。
sit and on bring the patient back the next day.
所以你可以快速完成所有操作。
So you can do everything quickly.
另一个优势是，PIB的信号比氟化示踪剂更清晰，这很有帮助。
And another advantage is that PIB has a very clearer signal than the fluorinated tracers, which is helpful.
信噪比通常会稍高一些。
The signal to noise ratio tends to be a little bit higher.
因此你能获得更清晰的读数，这对年轻人很有帮助。
So you get a clearer read, which is helpful for people who are younger.
因为我们并不将其用于诊断。
Because we're not using it diagnostically.
我们用它来做研究，而读数更清晰一些。
We're using it for research and the read is a little cleaner.
我认为我们能得到更好的信噪比。
We get a better signal to noise ratio, I think.
但其他人也这么认为。
But other people think it too.
这完全取决于你是否需要制备它。
It's all a matter of whether or not you need to make it.
你需要在附近拥有一台回旋加速器。
You need to have a cyclotron right there.
你需要一位化学家为你制备它，然后立即跑上楼进行注射，因为它衰变得非常快。
You need to have a chemist that can make it for you and then just run upstairs and you inject because it decays really quickly.
因此，你需要在本地具备强大的核医学能力。
So you need to have this big nuclear medicine capability on-site.
如果你更倾向于使用可以商业购买的氟化示踪剂，那也完全没问题。
If you prefer to use a fluorinated tracer that you can buy commercial, then it's perfectly fine.
但这些就是我们目前进行的所有扫描。
But this is all the scans that we are doing.
现在，我对此非常兴奋，我们还在进行大脑雌激素成像。
And now, I'm really excited about this, we're also doing brain estrogen imaging.
这是长期以来人们首次尝试测量大脑中的雌激素和激素。
So this is the first time that people have been trying to measure estrogen and hormones in the brain for a really, really long time.
由于多种原因，这非常困难。
It's very hard to do it for a number of reasons.
早在2019年，我去拜访了我的放射化学部门，告诉他们我们认为绝经对女性患阿尔茨海默病的风险至关重要。
Back in 2019, I went to my radiochemistry department, and I said, we think that menopause is very important for Alzheimer's risk for women.
我们假设，正是雌激素水平的下降导致了女性细胞老化加速以及阿尔茨海默病生物标志物风险的增加。
And we assume that is the decline in estrogen levels that drive the increased cellular aging and biomarker risk of Alzheimer's in women.
但这需要被证实，因为我们目前所有的信息都来自大鼠实验。
But that needs to be proven because all the information we have is from rats.
所以我们需要观察女性体内究竟发生了什么。
So we need to see what happens in women.
同时，我们还需要一种工具来测量激素疗法在大脑中的作用。
And we also need a tool to measure what hormone therapy is doing in the brain.
他们对我说：这听起来确实非常棒，但我们目前还没有这样的技术。
And they said to me, Well, that sounds really, really great, but we don't have it.
抱歉，你是想测量雌激素水平，还是雌激素受体的密度？
And sorry, you wanted to measure estrogen or estrogen receptor density?
我想同时测量两者。
I would like to measure both.
我今天能测量的是雌激素受体密度。
What I can measure today is estrogen receptor density.
好的。
Okay.
所以我们做的方法是，使用雌二醇，并用氟-18分子标记这种激素。
So what we do is that we have estradiol and we label estradiol, the hormone, with a Flutin-eighteen molecule.
它只是连接在雌二醇上。
It's just attached to the estradiol.
然后进行注射。
Then there's an injection.
雌二醇进入体内，但会在大脑中积聚。
The estradiol goes in the body but accumulates in the brain.
它的原理是，这个小分子模拟雌二醇本身，并寻找目标。
And the way it works is that this little molecule mimics estradiol itself and looks for the target.
我认为您的听众可能已经知道，激素的作用方式就像一把钥匙需要打开一把锁，而锁就是受体。
I think your listeners know this, but the way the hormones work is that the hormone is like a key that needs to open a lock, and the lock is the receptor.
每种激素都有其特定的受体。
And every type of hormone has a specific receptor.
所以雌激素有雌激素受体。
So estrogen has estrogen receptors.
孕激素有孕激素受体。
Progesterone has progesterone receptors.
这种示踪剂的工作原理被称为氟-18氟雌二醇。
The way that this tracer works is called fluorine 18 fluoro estradiol.
它进入大脑后会寻找雌激素受体。
That it goes up in the brain and it looks for the estrogen receptors.
它与受体结合，就像卡住了锁一样。
It binds to the receptors and it works like it kind of jams the lock.
因此，在雌激素存在期间，受体几乎被冻结在那一刻。
So the receptor just is almost frozen in time for the period of time that the estrogen is there.
然后，氟-18分子开始发射伽马射线。
And then the F-eighteen molecule starts shooting out gamma rays.
我们可以从外部拍摄这些射线的图像。
And we can take a picture of that from the outside.
接着，我们使用滤波反投影和其他技术来生成大脑的图像。
And then we use filter back projection and other techniques to get an image of the brain.
我们可以结合动力学模型，测量大脑每个区域的雌激素受体密度。
And we can use that with kinetic modeling to get a measure of estrogen receptor density in every part of the brain.
因此，我们终于能够做到这一点。
So we can finally do that.
就在2024年，我们发表了首个概念验证研究，证明我们可以获得信号，尤其是在垂体腺中，该信号具有特异性，不会受到代谢物或血管的干扰。
And just in 2024, we published the first proof of concept study showing that we can get a signal, especially in the pituitary gland where the signal is specific, like it's not confounded by metabolites or by blood band veins.
这并不违反直觉。
And this is not counterintuitive.
我的意思是，无论我们讨论的是哪种疾病，我们都预期垂体腺中雌激素受体密度很高，因为我们希望观察反馈机制。
I mean, we would expect to see a high density of estrogen receptors in the pituitary gland independent of the disease we're talking about just because we want to see the feedback.
我的意思是，我们可能会更期待在下丘脑看到它。
I mean, guess we'd expect to see it in the hypothalamus even more.
是的。
Yes.
因为我们需要获取促卵泡激素和黄体生成素的反馈。
Because we would want to get feedback for FSH and LH.
这是你的想法吗？
Is that your thinking?
是的，完全是我的想法。
Yes, totally my thinking.
血脑屏障是个大问题。
The blood brain barrier is a big issue.
但垂体稍微特殊一些，因为下丘脑在血脑屏障之外。
But the pituitary is slightly because the hypothalamus is outside.
对吧？
Right?
下丘脑在内部。
The hypothalamus is inside.
血脑屏障
Blood brain barrier
在外部。
is outside.
垂体是一半一半。
The pituitary is half and half.
是的。
Yep.
所以后部受到血脑屏障的保护。
So the back is protected by the blood brain barrier.
前部则没有。
The anterior part is not.
因此示踪剂很容易进入，这对我们很有帮助。
So the tracer goes in really easily, which is helpful to us.
是的。
Yep.
所以目前，我们就是这样做的。
So for now, this is what we're doing.
我们能够测量垂体中的雌激素受体密度。
We're able to measure estrogen receptor density in the pituitary.
再回到刚才那个问题。
Just go back to that for a second.
雌激素是如何穿过血脑屏障的，除了垂体那半个区域的通路之外？
How is estrogen getting across the blood brain barrier outside of that access to half of the pituitary?
存在转运体。
There are transporters.
那时间进程是怎样的？
And what's the time course?
所以如果你通过我的静脉注射我，需要多长时间才能到达？
So if you injected me in the arm through my IV, how long until it traverses?
而且它只在游离成分中转运吗？
And does it only traverse in the free component?
雌激素必须是未结合的，还是会与白蛋白或其他物质结合？
Does the estrogen have to be unbound or does it bind to albumin or something else?
它确实会结合。
It does bind.
是的。
Yes.
这就是为什么我们需要动力学建模。
That's why we need kinetic modeling.
所以这个过程的时间相对较快。
So the timing is relatively fast.
如果我们现在注射，几分钟内就能观察到摄取。
If we inject now, we can see uptake within minutes.
然后我们持续观察示踪剂在大脑中积累。
And then what we do is that we keep seeing the tracer accumulating up in the brain.
因此，我们绘制了脑内示踪剂摄取的时间-活性曲线，并与血液中示踪剂的动力学进行对比。
So we do a time activity curve of tracer uptake in the brain relative to the tracer kinetics in blood.
我们需要这两组数据，才能准确了解有多少示踪剂真正与受体结合、结合了多久，以及有多少只是被重新排回循环系统。
And we need both to get a good sense of how much is actually sticking to the receptors and for how long and how much is just pushed back into the circulation.
整个扫描时间为九十分钟，但摄取峰值出现在三十到三十五分钟之间。
So the whole scanning time is ninety minutes, but the peak of uptake is within thirty to thirty five.
所以我认为在十五到三十分钟之间，你能获得最强的信号。
So I would say between thirty and fifteen minutes is when you get the most signal.
然后你就开始达到饱和。
And then you start to saturate.
是的。
Yes.
此外，你还需要区分血流的影响。
Also, there's a component of blood flow that you need to disentangle.
我们使用了一整套数学模型。
There's a whole mathematical model that we're using.
这被称为洛根图。
It's called the Logan plot.
我的意思是，不知道你的听众是否想知道这些。
And I mean, don't know if your listeners want to know this.
我不知道他们是否想知道，但我确实想知道。
I don't know if they do, but I do.
好的。
Okay.
很好。
Good.
所以我们花了大量时间寻找一个适合建模的参考区域。
So what we do is then we have spent so much time trying to find a good reference region for the modelling.
因为如果你能找到一个已知不含或几乎不含雌激素受体的参考区域，
Because if you have a reference region that you know to be free or almost free of estrogen receptors
对。
Right.
这是你的阴性对照。
It's your negative control.
你可以将它减去。
You can subtract it out.
是的。
Yes.
这正是那个花了很长时间才解决的问题。
That's exactly the problem that it took a long time.
我们必须与临床前科学家、细胞生物学家、病理学家以及专门研究雌激素受体的人进行交流。
We had to talk to preclinical scientists, to cell biologists, to pathologists, to people who really specialize in the estrogen receptors.
我一直与迪亚兹·布里顿博士合作。
And I've been working with Doctor.
罗贝塔·迪亚兹·布里顿，她是我领域里的传奇人物。
Roberta Diaz Brinton, who's a legend in my field.
她已经从事这项工作四十年了，我不确定具体多久。
She's been doing this for, I don't know, forty years.
她对雌激素受体了如指掌。
She knows everything about estrogen receptors.
和她合作并研究所有尸检数据时，我们发现小脑皮层中有一个非常特定的区域。
And working with her and looking at all the postmortem studies, we found that there's a very specific part of the cerebellar cortex.
人们通常认为这个脑区主要参与运动控制，但实际上它具有多种不同功能。
Is this part of the brain that people say is mostly involved in movement control, but has a number of different functionalities.
在小脑的白质深处存在雌激素受体。
And there are estrogen receptors deep in the white matter of the cerebellum.
但如果你从侧面观察小脑，比如这样。
But if you look at, let's say this is the cerebellum from the side.
如果你观察小脑最下方的灰质层，也就是朝向后下部最薄的那一层，似乎那里 consistently 缺乏雌激素受体。
If you look at the inferior most part of the gray matter at the cerebellum, like the thinnest layer possible towards the posterior inferior part, that seems to be consistently void of estrogen receptors.
在那里发现的受体通常是β型受体。
Whatever receptors are found there tend to be beta receptors.
雌激素受体共有三种类型：α型、β型和GPR。
So there are three types of estrogen receptors, alpha, beta, and GPR.
我们使用的这种示踪剂专门针对雌激素受体α。
And this tracer that we use is more specifically looking for estrogen receptor alpha.
哦，有意思。
Oh, interesting.
所以你没有使用17β雌二醇？
So you're not using seventeen beta.
你用的是17α雌二醇？
You're using the seventeen alpha estradiol?
是的。
Yes.
哦，这很有趣。
Oh, that's interesting.
为什么？
Why?
我本来以为你会用β型。
I would have guessed you used the beta.
我可以长时间谈论这个话题。
I can talk about this for a very long time.
第一，它还没有被开发出来。
Number one, it's not been developed.
是的。
Yes.
尽管它是生物活性的雌二醇，对吧？
Even though it's the biologically active estradiol, right?
大脑。
Brain.
对。
Yeah.
但在肿瘤中不是这样。
But not in tumors.
有意思。
Interesting.
在肿瘤中的是α型。
In tumors is the alpha.
这些示踪剂是为肿瘤学开发的。
And these tracers were developed for oncology.
啊。
Ah.
是的。
Yes.
明白了。
Got it.
好的。
Okay.
是的。
Yes.
因为他们当然关心乳腺组织。
Because they, of course, care about breast tissue.
当然。
Absolutely.
对。
Yeah.
当然。
Of course.
是的。
Yep.
是的。
Yes.
是的。
Yes.
因此，为PET开发配体很难。
So it's hard to make ligands for PET.
这需要很多年。
It takes years and years.
你使用的是现成开发出来的工具。
You're working with what was developed off the shelf.
是的。
Yes.
基本上是重新利用了目前肿瘤学中常用的示踪剂，看看能否直接将其应用于大脑，我认为这是双赢的局面，因为我们不必重新发明轮子。
Basically repurposed a tracer that is commonly used now in oncology to see if we could just apply it to the brain, which I think is win win situation because we don't have to reinvent the wheel.
所以，通过使用这个参考区域，另一件需要做到的事情是信号必须保持一致。
So by using this reference region, the other thing that needs to happen is that the signal needs to be the same.
比如说，如果你研究的是绝经前、围绝经期和绝经后的女性，这个参考区域的信号必须保持稳定，这一点我们已经证实了。
Let's say if you're looking at women who are premenopausal, perimenopausal, postmenopausal, the signal in that reference region needs to be invariant, which we demonstrated.
因此，我们能够使用小脑——具体来说是小脑皮层的特定区域——作为参考，进行动力学建模。
Therefore, we were able to do a kinetic modeling using the cerebellum, that specific part of the cerebellar cortex as the reference.
通过这样做，我们发现垂体中的雌激素受体密度在围绝经期开始上升，但在绝经后反而更高，这完全违背了我们从前临床前研究中的认知。
And by doing that, we show the estrogen receptor density in the pituitary gland starts increasing during the perimenopausal window, but is actually higher after menopause, which goes completely against whatever knowledge we had from preclinical studies.
不过，我们不妨再仔细想想。
Although let's think about it for a second.
想想看。
Think about it.
好的。
Okay.
我不觉得这违反直觉，因为随着雌激素水平下降，
I don't know that I would think that that's counterintuitive because as estrogen levels decline,
你
you
几乎会预期垂体为了获得更多雌激素而上调受体表达，说：我需要更多，我需要更多，我需要更多。
would almost expect the pituitary in a greater and greater appetite for estrogen to upregulate expression of receptors to say, I want more, I want more, I want more.
我们知道它在拼命寻求雌二醇，因为它分泌的FSH和LH越来越多。
And we know that it's screaming for estradiol because it's secreting more and more FSH and LH.
所以，这是否就是你认为正在发生的情况？
So is that effectively what you think is happening?
我认为这就是正在发生的事，但在啮齿类动物中并不会这样。
I think that's what's happening, but that does not happen in rodents.
我们所有关于更年期的模型都基于动物模型的临床前研究。
All the models that we had for menopause are based on preclinical work in animal models.
在大鼠身上，大多数研究采用的是卵巢切除术。
And what happens in rats is that most studies utilize an ovariectomy.
也就是说，通过手术移除雌性大鼠的卵巢。
So it's a surgical removal of the ovaries of the female rat.
所以你是通过手术诱导更年期，是的。
So you induce menopause Yes.
手术，
Surgery,
研究发现，雌激素受体最初会过度表达，但随后会突然下降。
And what the studies have found is that there is an initial overexpression of the estrogen receptors, but then there's a sudden crash.
因此，治疗窗口非常狭窄。
So the window of opportunity is very narrow.
当把这一点应用到人类身上时，就像一个倒U形，但更像一个小小的高斯曲线。
And when you translate into human ears, there's like an inverted U shape, but it's more like a little, like a Gaussian curve.
这个窗口期如此狭窄，以至于在最后一次月经后的五年内，雌激素受体的密度就已经下降到原先的一半。
It's so narrow that within no more than five years after the final menstrual period, the idea is that the estrogen receptors have declined to half the density that they used to have prior.
这正是你对女性的预测。
And that's the prediction you would have had in women.
是的。
Yes.
但我们根本没发现这种情况。
But we didn't find that at all.
我们发现，直到65岁，雌激素受体的密度仍然保持得很好且很高。
We found that up to age 65, estrogen receptor density was still nice and high.
所以这完全跑题了，丽莎，但我只是想先把这一点搁置一旁，以便我们之后再回来讨论，希望我们两个人都能记得我接下来要提出的观点。
So this is totally off topic, Lisa, but I just want to park this on the side so that we can come back to it and hopefully between the two of us we'll remember what I'm about to suggest.
这难道不会潜在地表明，一位在十到十五年前就已绝经、且未接受绝经激素治疗的60多岁女性，仍然可以成为治疗对象，因为她显然在中枢神经系统中上调了雌激素受体，因此至少在生理上表明了她对雌激素的需求？
Would this not potentially suggest that a woman in her 60s who went through menopause ten to fifteen years sooner, who was not treated with menopausal hormone therapy would still be a candidate given that she clearly has upregulated her estrogen receptors in her CNS and therefore at least physiologically suggests an appetite for estrogen?
对。
Yes.
好的。
Okay.
我们会回头详细讨论这个问题，因为你知道，我们一直在反复强调现代医学的那些核心信条——即使有人终于开始承认，绝经期激素疗法可能并不是对女性最糟糕的处理方式，我这是在说反话。
We'll come back to that in detail because as you know, we just keep banging on all the greatest hits of the mantras of modern medicine which says, even if someone has finally come around to say maybe menopausal hormone therapy is not the worst thing you can do to a woman, I'm being facetious.
你最好在她一进入绝经期就给她使用。
You better give it to her the day she enters menopause.
天哪，我们绝不能去给那些已经六十多岁、十年前就被剥夺了激素的女性补充激素。
God forbid we take all of these women who are out there who are in their 60s who were deprived of hormones ten years ago and give them hormones.
她们的窗口已经关闭，门已经锁上了。
Their window is closed, the door is shut.
这正是我们担心的问题。
That was the concern.
事实上，在我们撰写这项研究的方案时，我对团队说，我们要选35岁和65岁的女性。
And in fact, when we were writing the protocol for this study, I said to my team, we're going to do 35, 65.
他们却说，也许我们应该选55岁？
And they're like, we should do maybe 55?
我说，不行，不行，不行。
I said, no, no, no.
我们要做65岁。
We're going to do 65.
我们要尝试描绘整个机会窗口。
We're going to try and map the whole window of opportunity.
他们说，我觉得这不太靠谱。
And they're like, I don't think that's a good idea.
有点太超前了。
It's a little bit far ahead.
当我和他们说，我们就这么干吧。
And when my and they said, well, we're just going to do it.
当结果陆续出来的时候，你知道，有时候你会有种预感。
When the results were coming in, you know when sometimes you have a feeling
不，对。
No, yeah.
有时候你必须相信自己的直觉，这是一个更有趣的问题。
Sometimes you have to trust your intuition and it's a more interesting question.
这是一个更有趣的问题。
It's a more interesting question.
我认为这是值得的。
I think it's worth it.
也许，显而易见，我们会集中在52到53岁左右，但让我们尝试覆盖极端情况，因为我们一直在讨论这个机会窗口。
Maybe, obviously, we will concentrate around age 52, 53, but let's try to map the extremes because we keep talking about this window of opportunity.
我们知道它是什么，但目前这种情况很特殊，因为我们还没有用生物指标来绘制它。
Like we know what it is, But it's peculiarative at this point because we have not been mapping it using biological indicators.
所以，不管怎样，我们做到了。
So anyway, we did it.
我认为这是值得的，因为显然研究中的所有女性都从未接受过激素治疗。
And I think it paid off because obviously all the women in the study are naive to hormone therapy.
所以没有人服用任何类型的激素。
So no one was taking hormones of any type.
这是否意味着那些绝经前的女性显然已经停用了口服避孕药？她们停了多久了？
Does that mean that the premenopausal women obviously were off And oral how long had they been off oral contraceptive?
在最初的研究中，有趣的是她们中的大多数人从未使用过避孕药。
In the very first study, it was interesting that most of them had never used breast control.
非常
Was very
有意思。
interesting.
所以，这确实是一个非常未经干预的群体。
So really, really a naive population.
在
At
至少三年，这是排除标准。
least three years, that was the exclusionary criteria.
而对于绝经后的女性，她们都从未使用过激素疗法。
And for the postmenopausal women, they were all never users of hormone therapy.
现在我们研究中已经有数百名女性，我们可以更加灵活地在统计上考虑不同因素，或者对过去使用过激素治疗者、从未使用者和当前使用者进行分层分析。
Now that we have hundreds of women in the study, we can be more flexible and account for different things statistically or try to stratify between past users or hormone therapy, never users, current users.
我们现在也有使用者了，这非常有趣。
We also have users now, which is very interesting.
那么你在使用者身上观察到了什么？
And what are you seeing in users?
这还没有发表。
It's not published yet.
所以我不确定我是否被允许谈论这个。
So I'm not sure that I'm allowed to talk about it.
但目前仅从轶事或描述性的角度来看，我们确实发现窗口发生了偏移。
But just anecdotally or descriptively for now, we do see that the window is shift.
曲线发生了偏移。
The curve is shifted.
因此，我们现在有了年龄超过65岁的女性，并且开始观察到雌激素受体的密度开始下降。
So we now have women who are older than 65, and we're starting to see where the estrogen receptors are starting to come down in terms of density.
但在使用激素治疗的人群中，目前看来，这条曲线并不会在那个年龄停止。
But in the hormone therapy users, for now, it seems like the curve does not stop at that age.
看起来密度似乎得到了保留。
It looks like maybe there is preservation of density.
那么问题来了，这是好事还是坏事？
And then the question is, is it a good thing or not?
因为我们不知道雌激素受体是否具有功能。
Because we don't know if the estrogen receptors are functional.
我们不知道转录通路是否仍按应有的方式运作。
We don't know if the transcriptional pathways are still working the way they're supposed to do.
我们是否在刺激那些并不发挥作用的受体？
Like are we stimulating receptors that are not functioning?
我们或许应该向人们解释一下我们的意思。
We should maybe explain to people what we mean.
那我们来互相启发，一起探讨一下吧。
So let's riff off each other on this.
但类固醇是通过驱动这些转录因子起作用的。
But steroids work by driving these transcriptional factors.
所以当雌激素或睾酮与受体结合时，真正重要的是它在细胞内做了什么，是的，没错。
So when estrogen or testosterone binds to receptor, what it's really doing, what matters is what it's doing inside the Yes, exactly.
它需要
It has
进入细胞，必须到达细胞核，与DNA结合，并发出指令：开始合成RNA，进而制造蛋白质，完成这些功能。
to go into the cell, it has to go to the nucleus, it has to bind to the DNA and it has to say, Hey, start making RNA that's going to make protein, that's going to do those things.
而真正重要的是转录和翻译的这个过程。
And it's that process of transcription and translation that matters.
所以你是在说，嘿，别太兴奋了，彼得。
And so what you're saying is, Hey, don't get too excited, Peter.
我们用这个检测方法只能确认激素是否与受体结合。
All we're able to check with this assay is does the hormone bind to the receptor?
这个检测无法衡量这种结合机制是否最终成功转化为蛋白质。
The assay can't measure whether the mechanism of that is translated all the way through to protein.
是的。
Yes.
因为其背后是一个系统。
Because the idea is then there's a system.
这是一个供需系统，大脑在需求激素，而卵巢则提供激素。
There's a supply and demand system, which is like the brain is calling for hormones and the ovaries are delivering the hormones.
只要反馈回路保持稳定，我们就能知道雌激素受体通常在正常发挥作用，比如增加大脑的血流、提升大脑的能量产生、增强免疫系统、促进神经可塑性和突触生长。
As long as the feedback loop is stable, we know that usually the estrogen receptors are doing what they're supposed to do, which is more blood flow to the brain, more energy production in the brain, a stronger immune system, more neuroplasticity, more synaptic growth.
但我们也知道，随着年龄增长和疾病发生，雌激素受体以及其他许多受体可能会开始失灵。
But we also know that with age and with disease, the estrogen receptors, as many other receptors, may start to malfunction.
它们也可能发生构象变化。
They may also go through conformational changes.
这意味着输出效果可能不再理想。
That means that the output may not be as good.
再多说说这一点。
Say more about that.
我的意思是，如果我对你说实话，这真是个令人恐惧的想法。
I mean, if I'm going to be honest with you, that's a terrifying thought.
我们能否从身体的外周部位找到一些线索，来帮助我们理解这个问题，因为在那里研究起来更容易？
What can we point to in the periphery to help us understand that where it's easier to study this question?
我在想氧化应激。
I was thinking oxidative stress.
好的。
Okay.
没错。
Right.
雌激素的一个功能是与线粒体中的雌激素受体结合。
So estrogen, one functionality that estrogen does is to attach itself to estrogen receptors in the mitochondria.
线粒体是身体每个细胞（包括神经元）的能量工厂。
And the mitochondria are the energy factory of every cell in the body, including neurons.
线粒体的作用是将能量转化为ATP，或者利用葡萄糖代谢的副产物。
What the mitochondria do is that they transform energy into ATP, or they take the byproduct of glucose metabolism.
还有一个叫做电子传递链的结构，它在产生ATP的同时也会产生氧化应激和自由基。
And there's a structure called the electron transport chain that produces oxidative stress and free radicals at the same time that they're making ATP.
通常情况下，平衡偏向于ATP的产生。
Usually the balance favors ATP.
但如果雌激素受体发生构象变化，可能会导致平衡变得不利，使得产生的氧化应激相对于ATP的生成量更多。
But if the estrogen receptors change conformation, that may lead to a less favorable balance where more oxidative stress is being produced relative to the amount of ATP that is being made.
所以是的，能量仍在产生，但氧化应激增加了。
So yes, there's still energy that's being produced, but there's more oxidative stress.
这在大脑中是个问题。
And this is an issue in the brain.
但难道就没有其他解释能说明为什么我们在那里看到电子传递链效率低下吗？
But couldn't there be other explanations for why we see the inefficiency of the electron transport chain there?
比如，我在想一些更基本的东西。
Like I'm thinking of something even more basic.
我们能不能对35岁、45岁和65岁的女性做类似的实验，在外周组织中观察雌二醇给药后某种非常直接的mRNA表达变化？
Couldn't we do a similar experiment of 35, 45, 65 year old women and look at the periphery and look at mRNA expression of something very straightforward in response to estradiol administration.
所以你找一群从未接受过激素治疗的女性，给她们全部注射雌二醇，然后在同等剂量的雌二醇下，测量我们预期会产生的mRNA量。
So you take hormone naive women, inject all three of them with estradiol and measure for equal amounts of estradiol how much mRNA gets produced for something that we would predict.
这是一项临床试验。
That's a clinical trial.
是的。
Yes.
但根据这个假设，我们会预期看到mRNA水平下降，这至少可能表明某些因素发生了变化。当然，如果想让这项研究更出色，你仍然需要做标记实验，以确保结合量至少是相等的。
But according to this hypothesis, we would expect to see declining mRNA, which would suggest at least possibly that something And of course, to make it a really cool study, you'd still want to do the labeling study to assume you're getting at least equal amounts of binding.
你需要进行归一化。
You would normalize.
你基本上会说：我要把结合信号的强度与产生的mRNA量进行归一化处理。
You would basically say, Look, I'm going to take the strength of the binding signal and I'm going to normalize it to the mRNA that comes out.
是的，如果你有资金的话，确实可以这么做，你知道，经费支持。
Yeah, you could if you had the money You know funding money.
哦，这个可不行。
Oh, not for this.
这是个有趣的问题，而且
That's an interesting question and it
有太多有趣的问题了，
There are so many interesting questions that
这些都不是关键问题。
this are not a jugular question.
是的。
Yeah.
这个问题暗示了：我们能否用更多的雌激素来解决这个问题？
This question implies, can we throw more estrogen at the problem?
事实上，正如你所知，在大脑之外的外周组织中，研究表明时机非常重要。
In fact, as you know about the periphery before the brain, studies have shown that timing is really important.
因此，如果你有健康的神经组织，并引入雌激素，雌激素对神经元是有支持作用的。
So if you have tissues, neuronal tissues that are healthy, and you introduce estrogen, estrogen is supportive of the neurons.
但如果神经元已经病变，存在缺血性损伤、组织周围有淀粉样病理变化或神经元内有缠结，那么雌激素会加重病情。
But if the neurons are diseased, if there is ischemic damage, there's amyloid pathology surrounding the tissues or tangles inside the neurons, then estrogen makes it worse.
有什么证据支持这一点？
What's the evidence for that?
是布林顿医生多年前做的那些研究，探讨了雌激素对线粒体功能的影响。
Is the studies that Doctor.
布林顿医生多年前做的那些研究，探讨了雌激素对线粒体功能的影响。
Brinton has done many years ago looking at how estrogen impacted mitochondrial function.
这特别指的是线粒体，但临床研究中也有类似证据，比如你非常精辟地分析过的女性健康倡议研究。
This is specifically mitochondria, but there seems to be evidence for that in clinical studies as well, like the Women's Health Initiative, which you have very elegantly unpacked.
在激素疗法与大脑健康方面，年龄与获益/风险比显然存在关联。
There's clearly an age related benefit to risk ratio when it comes to hormone therapy and brain health.
许多人认为，女性健康倡议研究中记忆子研究专门考察痴呆发病率的那些女性，当时已经太老了，不适合开始接受激素疗法。
And many people have argued that the women in the Women's Health Initiative, the memory study component that looked specifically at dementia incidents, those women were potentially too old to start taking therapy, hormone therapy, at that age.
当然，如今临床上我们并不使用不同配方或更高剂量的激素。
Granted, different formulations, higher doses of hormones is not what we do clinically today.
尽管如此，它还是证实了这种时间窗口假说，特别是对于那些核磁共振扫描显示存在（不一定是病理本身，而是例如血管性病变或白质高信号）证据的人群。
Nonetheless, it confirmed this kind of timing hypothesis, especially for those whose MRI scans showed evidence of an existing, not the pathology necessarily, but for instance, vascular lesions or white matter hyperintensities.
在亚组分析中，其观点是，那些大脑中已存在损伤的女性，对激素治疗的反应可能与大脑健康状况良好的女性不同。
In subanalysis, the idea is that women who already harbor damage in their brains may not be responsive to hormone therapy the same way that women with healthier brains would be.
这一点还有待完全证实。
This is completely to be demonstrated.
所以有两个评论。
So two comments.
首先是，你认为我们对这一主题的两种不同变体是否有清晰的认识？
The first is, do you think we have a sense of the difference between the two variations on that theme?
一种变体是，一旦疾病已经发生，雌激素不太可能逆转它，但这与雌激素会加剧疾病是不同的。
One variation is once disease has set in, estrogen is unlikely to reverse it, but that's different from estrogen will exacerbate it.
是的。
Yes.
让我们来详细分析一下。
Let's unpack that.
这是不同的。
It's different.
第二个是，正如你所指出的，在妇女健康倡议研究中，我们使用的是口服结合型马雌激素，这种激素已知会轻微增加凝血风险，而这对于加剧伴随该疾病的血管病变无疑是一个巨大隐患。
The second is, as you pointed out, in the Women's Health Initiative, we were dealing with oral conjugated equine estrogen, which is known to actually slightly increase coagulation which of course would be an enormous concern for exacerbating the vasculopathy that would accompany this disease.
因此，我们在使用外用雌二醇时完全看不到这种现象。
And therefore, whereas we don't see that at all with topical estradiol.
我们没有看到任何血管病变增加的证据。
We don't see any evidence of an increase in vasculopathy.
我们也没有看到动脉粥样硬化性心血管疾病风险的增加。
We don't see any increase in ASCVD risk.
因此，我们或许可以推测，嗯，外用雌二醇更安全——‘更安全’这个词有点强，但确实
So therefore we might assume that, hey, topical estradiol is much safer, much is a strong word, but is
更安全——基本上比口服雌二醇更安全，
safer- Essentially, than oral estradiol,
而且我们可能不会看到这种风险。
and that we might not see that risk.
所以基于这两点评论——
So given those two comments-
还有孕激素。
And also the progestin.
说得对。
That's exactly right.
总的来说，我仍然认为，如果乳腺癌的发病率（虽然不是死亡率）有明显上升，最可能的罪魁祸首就是孕激素。
The progestin as a whole, I mean, my belief still remains that if there is some meaningful, clinically meaningful uptick in the incidence, though not mortality of breast cancer, the progestin is the most likely culprit.
还有对血管的损伤。
But also for vascular damage.
因此，妇女健康倡议中使用的MPA这种孕激素，后来被证明可能增加血管损伤的风险。
So the MPA, the kind of progestin that was used in the Women's Health Initiative has later on been shown to potentially increase the risk of vascular damage.
这就是我们不使用它的原因。
And that's the reason we don't use it.
是的。
Yeah.
再加上口服的结合型雌激素。
Couple that with conjugated equine estrogen taken orally.
正变得名声不好。
Are getting a bad rep.
它们仍然有其作用。
They still serve a purpose.
我希望看到更多关于特定类型激素疗法的研究，因为可供选择的方案非常多。
I would like to see more research done on the very specific types of hormone therapy because there are so many different options that one can work with.
我真正希望看到的是这些疗法对大脑的影响。
And what I would really like to see is what these therapies do in the brain.
因为你说的每一点都完全合理。
Because everything you said makes perfect sense.
但并不是我想看到它。
But it's not I been want to see it.
我们可以做到。
We can do it.
我们现在有这个工具了。
We have the tools now.
在你的研究中，显然你必须保持干净和尽可能整洁。
In your study, obviously, you have to be clean and as neat as possible.
所以你必须将所有人标准化到同一个水平。
So you have to normalize everybody to the same point.
假设你注射的是生物同一性物质，等等，你真的注射了吗？
Assume you were injecting a bio identical Well, actually, did you inject?
我们只注射配体。
We just inject the ligand.
是的。
Yes.
你从未
You've never
好的。
Okay.
明白了。
Got it.
然后我们与威尔康奈尔医学中心的更年期诊所合作，那就是我工作的地方，或者说是妇产科。
And then we work with the menopause clinic at Weill Cornet Medicine, which is what I work, or the Obagine Department.
我们现在有一些女性正在接受更年期激素治疗。
And we have women who are now going on hormone therapy for menopause.
绝大多数人使用经皮贴剂。
The vast majority use Transdermal.
是的。
Yes.
雌二醇，有时联合微粒化孕酮。
Estradiol with or without micronized progesterone.
孕酮。
Progesterone.
这算是标准治疗方案。
That's kind of standard of care.
但如今，情况并不总是如此。
Today, it's not necessarily always.
但我们招募来参与这项研究的女性，正如你所说，需要在所接受的治疗类型上保持相似。
But the women that we tend to recruit for this study, obviously, like you said, need to be similar in terms of what kind of therapy they're taking.
我也想看看结合型雌激素（CEE）的成分。
I also want to see the CEE's compound.
我想看看口服雌激素和其他剂型，看看我们是否能观察到不同的信号。
I would like to see oral estrogen and the other formulations and see if we get a differential signal or not.
是的，我认为这会非常有趣。
Yeah, I think that would be very interesting.
但我认为最重要的问题，可能还是要通过当前的治疗剂型来解答，也就是经皮雌二醇，以及你提到的口服微粒化孕酮。
But I think the most important question would probably be answered through the lens of the formulation of the day, which is going to be transdermal estradiol and as you said, oral micronized progesterone.
我在引导这个话题时做得不够好，因为我们都偏离了主线，深入到了这些细节中。
I've done a bad job of navigating on this journey because I've taken us so far off the path into these details.
但你看，你必须追随自己的内心热情。
But look, I think you have to sort of follow your bliss.
这真的非常引人入胜。
This is incredibly fascinating.
让我们把话题拉回表面，从深海回到普通人的层面。
Let's bring it back up for people to kind of the surface level from the ocean floor.
通过这次讨论，我们已经确认女性的大脑中正在发生某些变化。
We've established through this discussion that something is happening in the brain of a woman.
哦，对了，关于这个话题，我还想最后问一个问题。
Oh, by the way, meant to ask one final question on that topic.
你们有年龄匹配的男性对照组吗？
You had male controls, age matched?
哪个研究？
For which study?
是雌激素配体研究吗？
For the estrogen ligand study?
没有，我们只做了
No, we're Got doing only
它。
it.
好的。
Okay.
所以我想问一下，我们不知道在男性大脑中，雌激素配体是否保持恒定，或者我预测会随着年龄增长而略微上升，因为他的雌二醇会随着睾酮下降而减少。
So I was going to ask, so we don't know if in a man's brain the estrogen ligands remain constant or I would predict will go up slightly as he ages because his estradiol is going down with testosterone.
是的。
Yeah.
所以这个观点是，大脑通过增加雌激素受体的密度来补偿雌二醇水平和其他激素水平的变化。
So the idea is that the brain compensates for changes in estradiol levels and other hormone levels by increasing the density of the estrogen receptors.
通常，大脑非常喜爱稳定。
So when usually the brain really loves stability.
人脑天生就是为了维持稳定。
The human brain is built for stability.
因此，当激素在月经周期中波动时，总体浓度仍然是可预测的。
So when hormones are fluctuating throughout the menstrual cycle, the concentration overall is still predictable.
所以大脑只需付出很少的努力就能维持一定数量的受体。
So the brain needs to make very little effort to maintain a certain number of receptors.
所以这是另一件非常有趣的事情。
So this is another thing that is very interesting.
这些受体并不是仅仅在那里。
The receptors are not just there.
它们不是偶然存在于膜上或大脑中，而是大脑需要主动制造它们。
They just happen to be in the membranes or in the the brain needs to make them.
所以这是一个主动的过程。
So it's an active process.
当雌二醇水平升高时，大脑就需要制造更少的受体。
And when estradiol levels increase, then the brain needs to make fewer receptors.
我们观察到雌激素受体密度的下降。
We see this decrease in estrogen receptor density.
但当雌激素（雌二醇）水平下降时，大脑会进行代偿性调整，过量表达或制造更多这些受体，以便捕捉循环中每一丝雌二醇。
But when estrogen level estradiol levels come down, then there is this compensatory adjustment where the brain will overexpress or make more of these receptors in order to just grab every little bit of estradiol that is in the circulation.
问题是，这种机制在什么时候会失效？
The question is, when does this mechanism crash?
最终，雌二醇水平将长期处于低位，而大脑将不得不放弃，因为制造受体是一个代谢成本极高的过程。
Eventually, estradiol levels will be permanently low and the brain is gonna have to give up because making receptors is a very metabolically expensive process.
因此，最终会进入一个雌二醇水平低、雌激素受体也减少或消失的状态。
So eventually, there will be a state or a stage where estradiol is low and the estrogen receptors are low or gone.
但这个过程究竟发生在什么时候？
But when does that happen?
看起来是在65岁之后。
It's after 65, it seems like.
在我们的研究中，似乎也是在65岁之后。
In our studies, it seems to be after 65.
我现在正努力让更多人也使用配体。
And what I'm trying to do now is to get more people to also use ligand.
我们还在研发新的配体，以便能够靶向β受体，在大脑其他区域获得更清晰的信号。
And we're also working to make new ligands that could look at the beta receptors, that can give us better signal in other parts of the brain.
我们希望更精准地观察海马体、杏仁核、额叶皮层和后扣带皮层，获得更高的特异性和更好的信噪比。
Like we want to look at the hippocampus, the amygdala, the frontal cortex, posterior single cortex with higher specificity and better signal to noise ratio.
你的检测方法有多定量？
How quantitative is your assay?
这是完全定量的。
It's fully quantitative.
你知道什么会很酷吗？
You know what would be so cool?
首先，它会带来多少辐射？
First of how much radiation does it expose?
非常少。
Very little.
非常少。
Very little.
好的。
Okay.
多少毫西弗？
How many millisievert?
是六毫居里。
It's six millicuries.
这相当于六毫西弗吗？
Is that the equivalent to six millisievert?
不是。
No.
这更少。
It's That's less.
是0.6毫西弗吗？
That's 0.6 millisievert?
少于一毫西弗。
It's less than one.
是的。
Yep.
好的。
Okay.
这将是一个非常棒的研究。
This would be a very cool study.
纯粹出于好奇。
Just out of pure curiosity.
非常昂贵，所以你可能不会这么做。
Very expensive, so you might not do this.
我非常想招募一组35岁的女性，在她们每次来月经的那天进行扫描。
I would love to take a group of 35 year old women and scan every one of them the day they get their period.
然后每隔五天扫描一次，持续三十天。
And then every five days for thirty days.
哦，是的。
Oh, yes.
因为这正是你刚才描述的天然实验。
And just because that's your natural experiment of exactly what you just described.
这将在三十天内呈现出雌激素和孕激素在大脑中的绝对最高值和绝对最低值。
That is going to be the absolute highest, absolute lowest level of estrogen and progesterone in the brain in a thirty day window.
而且由于这是定量的，你现在可以真正了解这种补偿发生的速度有多快，以及最高值和最低值分别是多少。
And the fact that it's quantitative means you can now really develop a sense of how quickly can this compensation occur and what's the highest high and the lowest low.
是的。
Yes.
然后将这与血液中的雌激素水平进行比较。
And then compare that to estrogen levels in blood.
是的。
Yes.
我认为澄清一点非常重要：循环系统中的雌激素水平与大脑中的雌激素水平无关，或者关系非常小。
I think it's so important to clarify that estrogen levels in the circulation have nothing to do or very little to do with estrogen levels in the brain.
真的吗？
Really?
是的。
Yes.
哦，明白了。
Oh, okay.
那请你再多讲讲这一点。
So say more about that.
我认为，临床上我们面临的问题是，我们只能测量血液中的雌激素。
That's the problem that we're having, I think, clinically, is that we can measure estrogen in blood.
但这无法告诉你是否正在经历潮热、健忘或更年期的任何神经症状，因为
But that will tell you nothing about whether or not you're having hot flashes forgetfulness or any of the neurological symptoms of menopause because
因为我们不知道受体的密度。
Because we don't know the receptor density.
我们不知道受体的密度。
We don't know the receptor density.
而且，大脑中的雌二醇水平受到非常严格的调控。
And also the brain levels of estradiol are very highly regulated.
大脑中的所有激素基本上都受到保护，不受血液循环变化的影响。
And it's basically all the hormones in the brain are sheltered from changes in the circulation.
所以这些转运体是活跃的？
So these transporters are active?
它们是活跃的。
They're active.
是的。
Yes.
大脑会需求激素。
The brain calls for hormones.
我们再来详细谈谈这个。
Let's talk more about that.
我以为这是被动扩散。
I thought this was like a passive diffusion.
不，不一定。
No, not necessarily.
在某些时期它可能是活跃的，而在其他时候则不是，这就是为什么你不能简单地把物质强行推入大脑。
There are periods of time where it could be in times where it's not, which is why you can't just push stuff inside the brain.
很难找到能进入大脑的示踪剂，因为大脑并不需要太多分子，很多物质根本无法通过。
It's so hard to get a tracer that goes in because the brain doesn't want a lot of molecules, a lot of things just can't come through.
这简直难以置信。
This is unbelievable.
是的。
Yes.
要提出这种大脑压力的概念真是太难了。
It's so difficult to come up with this brain stress.
所以你的意思是，如果我们进行我的思想实验——每五天或每天一次，这只是一个思想实验。
So you're telling me that if we did my thought experiment of every five days or every day, it's just a thought experiment.
每一天，你都在女性的整个周期中抽取她的血液，你会看到雌二醇从几乎为零上升到200，然后再降下来。
Every single day, you draw a woman's blood throughout her cycle and you're gonna see estradiol go from next to nothing to 200 and back down.
你在血液中确实能看到这一点。
You see that in blood.
是的。
Yes.
这正是我想说的。
That's what I'm saying.
关于 Bayt 播客
Bayt 提供中文+原文双语音频和字幕，帮助你打破语言障碍，轻松听懂全球优质播客。