与博士一起了解围绝经期和更年期对大脑的影响。路易莎·尼古拉

所以我们知道，大脑前部有大量雌激素受体。

So what we know is that s we have estrogen receptors that flood the frontal part of the brain.

大脑前部负责执行功能、思考和信息处理速度。

The frontal part of the brain is where we hold our executive functions, thinking, processing speed.

当这些雌激素受体因缺乏循环中的雌二醇而死亡时，雌激素不足会发生什么？

When those estrogen receptors die because there's no circulating estradiol, we don't have enough estrogen, what happens?

我们的思维会变得不那么敏锐，但这种情况也可能发生在皮质醇过高的状态下。

Well, our thinking is not the best, but it can also happen in a hypercortisole state.

如果你承受严重压力，短期记忆可能会受影响，但这也可能是脑雾的表现。

So if you are severely stressed, you may not have your short term memory, but that could also be brain fog as well.

所以，仅仅因为有脑雾，并不意味着你患有阿尔茨海默病或痴呆。

So it doesn't mean that you have Alzheimer's disease or dementia just because you have brain fog.

这只是一个症状，而且是可以改善的。

It's just a symptom, and we can fix that.

你之前说过，阿尔茨海默病不会在70岁突然出现。

You've said that Alzheimer's doesn't suddenly appear at 70.

不是。

No.

它其实早在我们三十岁和四十岁时就开始悄然发生了。

That it is actually starts quietly in our thirties and forties.

所以请为我们的听众详细解释一下，大脑里到底发生了什么。

So walk our listeners through, you know, what is actually happening in the brain.

所以我们有

So we've

这个三十年的进程。

got this thirty year projection.

对吧？

Right?

如果我们考虑阿尔茨海默病，它其实始于三十岁左右，因为通常会发生什么？

And Alzheimer's disease, if we think about it, it really starts in the thirties because what tends to happen?

嗯，这时我们的大脑已经完全发育成熟了。

Well, this is when our brain has fully formed.

我们已经在那里了。

We're already there.

所以从进化角度来看，好吧。

So the only thing evolutionarily is, okay.

很好。

Great.

我已经发育成熟了，现在该开始放松了。

I've I've formed, and now it's time for me to decompress.

由于大脑自然衰老的过程，我们的灰质会变薄。

And what tends to happen just due to the natural brain aging process, we get thinning of the gray matter.

我们有灰质和白质。

So we've got got gray matter and white matter.

如果我们不照顾好大脑，白质中就会出现小病灶。

And if we don't look after our brains, we get little lesions in the white matter of the brain.

随着我们年龄增长，很多事情变得至关重要。

And as we're getting older, we've got more things is of the essence.

我们没有像以前那样照顾好自己。

We don't have we're not looking after ourselves as much.

因此，所有那些有助于打造高效大脑、预防阿尔茨海默病的活动，我们都没有参与。

So all of the things that we're meant to be doing that build a high performing brain and that stave off Alzheimer's disease, we're not engaging in these activities.

我们不锻炼。

We're not exercising.

我们睡眠不足，无论是因为孩子、工作压力，还是其他压力因素。

We're sleep deprived, whether that's due to kids, whether that's due to work related, stress related, all of these things.

所以我们没有做那些真正为保护大脑而存在的事情。

So we're not doing the things that are there to serve and protect our brain.

如果二十年来我们都不这样做，大脑里就会发生这些变化：这些斑块——也就是淀粉样蛋白β和Tau蛋白缠结——开始积累并不断恶化。

And over the course of twenty years, if we don't do that, what happens in the brain, these plaques, okay, these these amyloid beta proteins and these tau tangles, they start to build up and they compound.

你在三十岁时并不会意识到这一点。

And you don't realize it in your thirties.

我现在就可以扫描你的大脑，也可以扫描我的大脑。

I may scan your brain right now, and I could scan my brain.

我们大脑中可能已经积累了淀粉样蛋白和一些tau蛋白残留。

We probably got amyloid built up in the brain and some tau residue.

我们很可能已经这样了。

We probably have.

我不知道你是否睡眠不足，但我们身在纽约市。

Because I don't know if you're sleep deprived, but we're in New York City.

空气中有很多毒素，而我们晚上会把它们清除掉。

There's a lot of toxins in the air, and then we wash it out at night.

但如果我们不这样做——你知道的，如果我们每晚都不睡觉，不清理那些淀粉样蛋白，它们就会累积。

But if we don't do that as we you know, if we don't sleep every night and we don't wash out those amyloid beta proteins, they compound.

它们会积累起来。

They accumulate.

它们开始占据大脑。

They start to take over the brain.

这会导致突触丧失，长期下来就会引发阿尔茨海默病。

It causes losses of synapses, and that over time causes Alzheimer's disease.

有没有一个阈值？

Is there a threshold?

也就是说，你需要积累多少才会开始出现这种情况？

Like, how much accumulation do you need before you start having this

就是阿尔茨海默病。

is Alzheimer's.

所以淀粉样蛋白β，好吧，我们来谈谈它。

So amyloid beta, okay, we'll we'll talk about it.

它曾被妖魔化为一种有毒蛋白。

It's a it's was demonized as this toxic protein.

嗯，是的。

Uh-huh.

我们现在知道它并不是一种有毒蛋白。

We know now it's not a toxic protein.

很糟糕，很糟糕。

Bad, bad, bad.

是的。

Yes.

因为我们过去认为阿尔茨海默病是淀粉样蛋白级联假说。

Because we used to think of Alzheimer's disease as the amyloid cascade hypothesis.

那就是它的定义。

That's what it was.

对吧？

Right?

但我们知道那并不是真相。

But we know that that's not it.

明白吗？

Okay?

淀粉样蛋白实际上是一种保护性分子。

Amyloid is actually a protective molecule.

对吧？

Right?

它实际上是用来保护你的大脑的。

It actually is served to protect your brain.

也许你听说过这个。

Maybe heard this.

是的。

Yeah.

当我们激活先天免疫系统，感到压力时，神经元会开始释放淀粉样蛋白，以保护神经元免受伤害。

So when we activate our innate immune system, when we get stressed, the neurons start releasing amyloid as a way to shield the neurons to protect them.

但问题是，我们需要在夜间拥有一个良好的清除系统，也就是当我们进入深度睡眠时，将它清除掉。

But what happens is we have to have a good clearance system at night, which is when we go into deep sleep to clear it out.

这就是淀粉样蛋白β。

That's amyloid beta.

它存在于神经元外部，明白吗？在脑脊液中。

It lives outside of the neurons, okay, in the cerebral spinal fluid.

然后我们还有tau蛋白。

And then we have tau proteins.

现在我不确定你是否知道，但我推测70%的女性患有阿尔茨海默病的原因之一，是因为我们比男性更容易受到tau蛋白的影响。

Now I don't think you I don't know if you know this, but the one of the reasons that I hypothesize that seventy percent of women have Alzheimer's disease is because we are more predisposed to tau proteins than men.

好的。

Okay.

是的。

Yeah.

给我详细讲讲这个。

Walk me through this.

所以tau蛋白存在于微管中。

So tau protein lives in the microtubules.

让我们来谈谈神经解剖学，我们现在大约有870亿个神经元。

Let's neuroanatomy right now, we have around 87,000,000,000 neurons.

好的。

Okay.

每个神经元大约有15000个连接。

Each neuron has around 15,000 connections.

好的。

Okay.

我想象神经元就像一颗星星，带着一条长尾巴，底部还有一个小星星。

I think of neuron as a star with a long tail and then a little star at the bottom.

没错。

There you go.

我喜欢这个说法。

I love that.

所以这个星星，我可以把它想象成一棵树。

So that star, I can think about it like a tree.

明白吗？

K?

所以这个星星是神经元的细胞体，然后你有轴突。

So that star is the neuron cell body, and then you've got the axon.

明白吗？

Okay?

所以这就是树干。

So that's the trunk.

而在这根轴突内部，就像有高速公路一样。

And that axon within that live these highways, if you will.

我们就是在这里传递信息的。

And this is where we send information.

信息处理速度会提高，也就是传导速度。

Information processing speed goes up, that conduction velocity.

微管就存在于这里，tau蛋白也在这里。

That's where the microtubules live, and that's where tau protein lives.

现在，tau蛋白一旦被磷酸化，嗯。

Now tau protein, once it is phosphorylated Mhmm.

明白吗？

Okay?

它就会从微管上脱离，并开始聚集。

It breaks off the microtubules, and it starts to aggregate.

当它在大脑的这一区域开始形成团块时，轴突就会发生塌陷。

And when it starts to form clumps in that in that part of the brain, that's when we get collapses of the axon.

这真的很有趣。

This is really interesting.

因此，有一种酶负责这一过程，那就是GSK-3β。

So there is an enzyme responsible, GSK three beta.

它是一种实际对tau蛋白进行磷酸化的酶。

It's an enzyme that actually phosphorylates the tau protein.

明白吗？

Okay?

因此，它会导致tau蛋白在此处过度磷酸化。

So it causes it to become hyperphosphorylated within that.

当它变得过度磷酸化时，就会导致轴突塌陷。

And when it becomes hyperphosphorylated, it causes the collapse of the axon.

你听好了。

Get this.

雌激素、孕激素和催乳素

Estrogen, progesterone, and prolactin

比如，激素和这个过程有关吗？

say, like, does hormones have anything to do with this process?

孕激素和催乳素，嗯。

Progesterone, and prolactin Mhmm.

抑制这种酶，从而使其失活。

Inhibit that enzyme, so it shuts it off.

因此，雌激素、孕激素和催乳素实际上会阻止tau蛋白的磷酸化。

So estrogen and progesterone and prolactin actually stop the phosphorylation of that tau.

明白。

Okay.

那么围绝经期会发生什么？

So what happens during perimenopause?

我们失去了雌激素的支持，因此现在会过度聚焦于这一点。

We don't have the support of the estrogen, so we are now hyperfixated on that.

因此，由于失去了这种支持，我们患上过度磷酸化的风险增加了。

So we have an increased risk of getting hyperphosphorylated because we don't have the support anymore.

那么睡眠时的类淋巴系统，也就是每晚的清理过程，是清除tau蛋白，还是只清除淀粉样蛋白？

And does the the the sleeping the glymphatic system, you know, the nightly washout, does it clear the tau proteins or just the amyloid?

只清除淀粉样蛋白。

Just the amyloid.

因为在睡眠期间，我们会激活——

Because during sleep, we activate yeah.

所以我们激活了类淋巴系统。

So we activate the glymphatic system.

我们身体里有一个淋巴系统，但真正起作用的是胶质细胞，这就是来源。

We've got a lymphatic system in our body, but what happens is the glial cells, that's where it comes from.

胶质细胞这个词源自希腊语，意思是‘胶水’。

Now glial cells comes from the Greek word glue.

它们位于神经元之间，在深度慢波睡眠时会缩小体积。

They stick between neurons, and they shrink in size during deep slow wave sleep.

所以当它们收缩时，脑脊液就能流经大脑，清除淀粉样蛋白。

So when they shrink, what happens, we can get all of the cerebral spinal fluid to wash through the brain and clear out the amyloid.

因此它能清除淀粉样蛋白，但无法清除tau蛋白。

So it clears out the amyloid, but it doesn't clear out the tau.

这正是我目前的假设。

This is what I'm hypothesizing right now.

我正在进行一项元分析，你可以理解为对所有可用证据进行的庞大而复杂的统计分析。

I'm doing a meta analysis, which you can understand is a really, really big, statistical analysis of all of the available evidence.

但我假设，我们女性比男性积累更多的这种tau蛋白，可能与80%的自身免疫疾病发生在女性身上有关。

But I'm hypothesizing that this tau protein that we accumulate more so than men has something to do with the fact that 80% of all autoimmune diseases are female.

嗯。

Mhmm.

因为如果你思考自身免疫疾病，比如多发性硬化症。

Because if you think about autoimmune diseases, let's talk about multiple sclerosis, for example.

那它是什么？

What is that?

这是一种脱髓鞘疾病，我做过很多

It's a demyelinating disease, and I have done a lot

你的肌电图研究。

with you EMG studies.

护士。

Nurse.

是的。

Yeah.

脱髓鞘。

Demyelinization.

所以，髓鞘，是的。

So the myelin sheath Yes.

是包裹神经元的绝缘层。

Is the insulation around the neurons.

绝缘层越多，神经元之间的电信号传递就越快。

It allows the more insulation you have, the faster the electrical impulses travel between neurons.

是的

Yep.

好的

Okay.

当我们脱髓鞘时，嗯

When we demyelinate Mhmm.

我们移除了绝缘层，这是一种自身免疫性疾病，会导致这种情况发生。

We remove the insulation and there's an autoimmune disease that will cause that to happen.

嗯

Mhmm.

然后这些神经传导时间就会变慢。

And then those nerve transduction times will slow down.

因此，多发性硬化症患者会出现这些身体缺陷。

So people with MS will have these physical defects.

是的

Yeah.

你知道吗？

You know?

或者他们感觉不到，或者很吃力。

Or they can't feel or they're struggling.

他们会出现足下垂或眼睑下垂。

They get foot drop or ptosis in the eye.

我们在肌电图上看到的是传导减慢或完全传导阻滞。

And what we see on an EMG is conduction slowing or complete conduction block.

好的。

Okay.

我总是想，如果发生这种情况，肌电图是什么？

And I always think if that's happening And what's an EMG

对听众来说是什么意思？

for the listeners?

肌电图。

Electromyography.

所以这是一个针头，会插入到一根神经纤维中，我们可以检测神经冲动的传导速度。

So it's a needle which you'll stick into one of the nerve fibers, and we can check the the the speed of impulses.

而且是

And is

这就是诊断多发性硬化症的方法吗？

that how we diagnose MS?

是的。

Yeah.

好的。

Okay.

确实是。

It is.

以及其他神经影像学检查。

And other neuroimaging studies.

我推测这可能是某种原因，你知道的，因为我们仍然不知道为什么。

And I I hypothesize that this is some you know, because we still don't know why.

为什么百分之八十的自身免疫性疾病都发生在女性身上？

Why don't why why are eighty percent of all autoimmune diseases women?

我们仍然不知道原因。

We still don't know why.

你觉得这是为什么？

Why do you think that is?

嗯，这是我的一个假设。

Well, this is, this is one of my hypotheses.

这还没有被证实，只是我个人的推测。

It hasn't been this is just me speculating.

不。

No.

为什么我们没有深入研究到能够弄清楚这个问题？

Why why haven't we studied it to the point that we would know

答案？

the answer?

因为女性的研究不足，被忽视，因为她们有激素周期，这让研究变得困难。

Because women are understudied, under researched because they have a hormonal cycle which is Makes them hard.

是的。

Yes.

让她们难以应对。

Makes them hard to deal with.

所以，我们积累了大量的tau蛋白，是的。

So So we've got the accumulation of tau Yeah.

以及大脑中的淀粉样蛋白β。

And amyloid beta in the brain.

因此，还有几种机制。

And so there's several mechanisms too.

所以你会想，好吧。

So then you think, okay.

那么，阿尔茨海默病的整个过程，难道仅仅通过阻止淀粉样蛋白和tau蛋白就能制止吗？

Well, is the whole process of Alzheimer's disease not getting it just to stop the amyloid and tau protein?

不，不是这样的。

Well, no.

因为阿尔茨海默病中，当淀粉样蛋白堆积时，它会阻断神经元之间的连接。

Because what happens in Alzheimer's disease, that amyloid, when it builds up, it stops the connections between neurons.

嗯。

Mhmm.

明白吗？

Okay?

所以，这就是阿尔茨海默病的真正本质。

So that's what Alzheimer's disease really is.

神经元之间的连接原本有大约一万五千个，但会减少到五千个。

You've got these connections in the neurons, and these connections go from 15,000 connections to 5,000.

这些连接负责我们所有的行为、感受和思考方式，这会导致记忆问题和短期记忆丧失。

And those connections are responsible for everything we do, your actions, the way that you feel, the way that you think, and that causes memory complaints, short term memory loss.

阿尔茨海默病中首先受到影响的区域是海马体，这是一个形似海马的结构。

And the first area to go in Alzheimer's disease is the hippocampus, which is this seahorse shaped structure.

我们每个人都有一个。

We all have one.

它位于颞叶深处，就在耳朵后面。

It's deep in the temporal lobes just behind the ears.

它得名于此。

And it got the name.

它的拉丁文名字叫海马，因为它的形状就像海马，而它储存着我们的记忆。

It's a Latin name for seahorse because that's what it looks like, and that holds our memories.

记忆的形成与巩固，这是我们随着年龄增长最先衰退的部分，但也发生在

Memory formation, memory consolidation, and that is the first thing to go as we as we get older, but also during

也会影响你的皮肤。

affect your skin too.

随着中年时期雌激素水平下降，你的皮肤会失去胶原蛋白、水分和弹性。

As estrogen drops in midlife, your skin can lose collagen, hydration, and elasticity.

这就是Alloy Health的用武之地。

That's where Alloy Health comes in.

Alloy 让基于证据的更年期护理触手可及，帮助女性连接更年期专家。

Alloy makes evidence based menopause care accessible, connecting women with menopause experts.

现在，他们通过 M4 重新定义了护肤，这款处方产品含有雌三醇——一种仅作用于皮肤的雌激素形式。

And now they're redefining skincare with M4, their prescription line made with estriol, a form of estrogen that only works on the skin.

最初推出的是 M4 面霜处方版，如今 Alloy 又推出了两款突破性产品：M4 面部精华处方版和 M4 眼霜处方版。

It started with the M4 Face Cream Rx, and now Alloys added two game changers, the m four face serum RX and the m four eye cream RX.

开始使用非常简单。

Getting started is easy.

前往 myalloy.com。

Head to myalloy.com.

那就是 myalloy.com。

That's myalloy.com.

回答几个简单问题，持证医生将审核您的信息。

Answer a few quick questions, and a licensed physician will review your info.

使用优惠码 M c h 20。

Use code M c h 20.

输入代码 MCH 20，首单立减 20 美元。

That's MCH two zero for $20 off your first order.

您的个性化护肤产品将直接配送到家。

Your personalized skin care ships right to your door.

无需预约，无需排队取药。

No appointments, no pharmacy lines.

因为您的皮肤在变化，您的护肤流程也应随之调整。

Because your skin's changing and your routine should too.

访问 myalloy.com 并使用代码 MCH 20。

Visit myalloy.com and use code MCH 20.

代码是 M C H 二零。

That's m c h two zero.

当我们讨论心理健康与认知衰退之间的潜在关联时，许多持怀疑态度的人会试图否认激素与此有关，声称这仅仅是衰老所致。

So a lot of the naysayers when we talk about the possible connection with mental health and especially in cognitive decline will try to negate hormones having anything to do with this and say, this is just aging.

不对。

No.

痴呆症和阿尔茨海默病并不是大脑自然衰老的一部分。

Dementia and Alzheimer's disease is not part of the natural brain aging process.

你可以活到一百岁，同时保持认知功能完好。

You can get to a 100 years old and keep and and have your cognitive functions intact.

这是可能的。

It is possible.

这很难，但确实可能。

It is hard, but it is possible.

嗯哼。

Mhmm.

荷尔蒙是其中一个因素。

Hormones are one factor.

导致阿尔茨海默病的途径有很多。

There are many pathways to getting Alzheimer's disease.

如果你是二型糖尿病患者。

If you're type two diabetic.

男性也会得，但男性更有保护性。

Men get it, but men are more protective.

明白吗？

Okay?

他们拥有更强的认知储备。

They have greater cognitive reserve.

他们经历男性更年期的时间更晚、速度更慢，但同时也拥有更多的睾酮。

They go through andropause that are at a much later stage, slower rate, but they also have more testosterone.

而睾酮会转化为雌激素。

And testosterone aromatizes into estrogen.

雌激素具有保护作用。

And estrogen is protective.

雌激素非常具有保护性。

And estrogen is very protective.

那请解释一下绝经前的大脑、围绝经期的大脑是什么样的。

So walk me through a premenopausal brain, a perimenopausal brain Mhmm.

以及绝经后的大脑。

And a postmenopausal brain.

绝经前的大脑功能正常。

So the premenopausal brain has everything functioning adequately.

对吧？

Right?

取决于生活方式，但我们就假设你过着非常健康的生活。

Depending on lifestyle, but let's just say you're living just, you know, a really great healthy life.

你的大脑得到了雌激素的滋养。

You've got your your brain is getting fed with estrogen.

这是第一点。

That's the first one.

孕激素、催乳素和睾酮。

Progesterone, prolactin, and testosterone.

这些激素我不说像是大脑的肥料，但它们在调控许多通路。

These are I wouldn't say they're like fertilizer for the brain, but they are mediating many pathways.

所以你的大脑有着正常的葡萄糖代谢。

So you've got proper glucose metabolism in the brain.

大脑的主要能量来源，它是一个耗能巨大的器官。

The brain's primary fuel source, it's a hungry organ.

明白吗？

Okay?

只占你总体重的2%，却消耗了你摄入总能量的20%

2% of your total body weight but consumes 20% of the total energy that you take

。

in.

非常有趣。

Fascinating

对我来说。

to me.

为什么呢？

Why is that?

因为大脑需要大量的能量来运作。

Because it takes so much to power.

它只是

It just

它全天候不停地工作。

go it's going twenty four seven.

大脑是个耗能巨大的器官，所以需要持续供能。

It's such a hungry organ, so it needs fuel.

它从哪里获取能量？

Where does it get its fuel from?

它使用葡萄糖。

It uses glucose.

雌激素有助于调节血液中的葡萄糖，使其进入神经元和细胞体，供我们使用。

Estrogen helps mediate glucose that's in your that's in your blood, get into the neuron so we can use it, get into the cell body.

这样我们就能维持认知功能正常。

And what happens as we so we can use so that means we have our cognitive functions intact.

我们拥有大量的能量。

We've got a lot of energy.

我们在二十多岁时可以出去玩，把自己累垮，第二天还能起来跑个马拉松。

We can go out in in in our twenties and and and ride ourselves off and wake up and do a marathon the next day.

嗯。

Mhmm.

我知道我22岁的时候就这么做过。

I know I did that at at 22.

所以当我们开始看到雌激素水平下降时，就意味着我们的大脑不再像以前那样得到支持了。

So when we start to see this dip in estrogen, that means our brain isn't as supported as what it once was.

明白吗？

K?

因此，我们的葡萄糖代谢不再像以前那样有效了。

So our glucose metabolism isn't working as well.

我们称之为

We name

在大脑中。

In the brain.

在大脑中。

In the brain.

实际上

Actually

在身体的所有部位

in in all parts of

的身体。

the body.

是的。

Yeah.

有些女性夜间会出现潮热，这会导致她们夜间醒来，因此出现睡眠中断，而这也导致了β-淀粉样蛋白的积累。

Some women get hot flashes at night, which is waking them up during the night, and they were therefore, you get sleep disruption, which is also accumulating amyloid beta.

由于激素的影响，我们对压力的耐受性更低，k。

We have higher we have a lower tolerance to stress, k, because of hormones.

当我们进入那个阶段时，正如你自己所说，这虽然不是我的专业领域，但你提到我们有一个干预的窗口期。

And then when we get to that stage, like you've you've said it yourself, and it's not my wheelhouse, but you said that we've got a window of opportunity to intervene.

当我查看相关研究时，特别是针对APOE4携带者——他们占人口的百分之二十，属于纯合子——这些女性正是最易受到这一窗口期影响的群体。

And when I look at the studies, especially for APOE four carriers, which represents twenty percent of the population, homozygous, these are the women who are who are most vulnerable to that window of opportunity.

这项研究来自斯堪的纳维亚。

There that study came out of Scandinavia.

对吗？

Right?

是的。

It did.

是的。

Yeah.

是的。

Yeah.

这项研究显示，携带一个风险基因拷贝的女性。

Which showed that women who are who have one copy risk.

是的。

Yeah.

是的。

Yeah.

一个APOE四等位基因拷贝，嗯。

One copy of APOE four Mhmm.

患阿尔茨海默病的风险增加两到四倍。

Have a two to fourfold increase in getting Alzheimer's disease.

那么激素替代疗法或雌激素替代对她们有什么影响？

And then what did the HRT do for the or the estrogen replacement do for them?

它降低了她们的风险。

Well, it lowered their risk.

而且这仅限于那个机会窗口期内。

And that is and that's only during that that window of opportunity.

什么是这个窗口期？

What is the window?

早期。

Early.

现在还早。

It's early.

是的。

Yeah.

是的，现在还早。

It's yeah.

这大约是在绝经前十年左右。

Depending it's, like, ten years prior to menopause.

然后，这一点在心血管数据中也有体现。

When and then this is shown in cardiovascular data.

多年来，观察性研究早已表明这一点，而妇女健康倡议研究也证实了这一点适用于年轻患者。

We knew for observational studies for years, and the WHI did prove this for the younger patients.

我们有一个心血管干预的窗口期，是的。

We have a cardiovascular window of opportunity Yes.

在斑块形成之前就开始干预，可以预防斑块的积聚和钙化。

Too, where it is preventative for the plaque, you know, accumulation calcification if you get it started before the plaques form.

是的。

Yeah.

据我们所知，一旦斑块已经形成，这种方法就不太有效了。

It's not really helpful to the plaques once they're already formed as far as we understand.

对。

Yeah.

你可以把你的大脑想象成一辆一级方程式赛车。

Basically, think of your brain like a Formula one car.

好的。

Okay.

对吧？

Right?

如果你不用优质燃油来为这辆一级方程式赛车加油，而是用廉价汽油，最终它就会停止运转——如果你不再加油，它就无法高效运行。

And if you're not fueling the Formula one car with proper gas and you're doing the the cheap gas and then eventually it just stops working, you just don't put the gas in anymore, it's not going to go efficiently.

当我们谈论雌激素、雌激素替代疗法和激素替代疗法时，你所做的并不是什么奇迹。

When we're talking about estrogen and estrogen replacement therapy and hormone replacement therapy, what you're doing is I don't call it's not a miracle.

它只是辅助你完成对大脑必要的其他事情。

It's an adjunct to help you do other things that are necessary for the brain.

它能帮助你去健身。

It's gonna help you go to the gym.

明白吗？

Okay?

多努力一点。

Push more.

它有助于提高骨密度。

It's gonna help with bone mineral density.

它有助于减少脂肪含量。

It's gonna help with lowering fat mass.

它有助于降低炎症。

It's going to help lower inflammation.

所有这些因素如果加剧，都会加重神经炎症和阿尔茨海默病。

All of these things that if are heightened can exasperate neural inflammation and Alzheimer's disease.

好的。

Okay.

所以就像是次要的。

So like a secondary.

没错。

Correct.

是的。

Yeah.

是的。

Yeah.

我们的许多听众都知道潮热是什么。

Many of our listeners know what hot flashes are

是的。

Yeah.

你知道并理解这些，还有情绪波动，但并不真正明白为什么认知功能会发生变化。

You know, and understand that and mood swings, but they don't understand really why cognitive function shifts.

所以你提到了神经和神经传导。

So you talked about the nerves and nerve conduction.

神经递质在这里扮演了什么角色？

Where do neurotransmitters play here?

天哪。

Oh my god.

这实际上非常有趣。

So this is actually really fascinating.

我不确定你是否听说过这个。

I'm not sure if you heard of this.

你知道下丘脑有一群被称为KINDY神经元的神经细胞吗？

Did you know that the hypothalamus has a cluster of neurons called KINDY neurons?

继续说。

Keep going.

是的

Yeah.

所以是 K-I-N-D-Y，但发音是 KINDY，代表 kisspeptin、神经激肽六和强啡肽。

So k I n d y, but it's pronounced KINDY, And it stands for kisspeptin, neurokinane six, and dynorphin.

好的。

Okay.

好的？

Okay?

这些神经激肽簇之所以重要，是因为新出现的神经激肽受体激动剂，比如苯基阿嗪，用于治疗潮热。

And these clusters of neurokinin only because the new neurokinin receptor agonists that have come out, phenylalazin, stuff to treat hot flashes.

所以这一簇神经元实际上有助于调节生殖和体温。

So this cluster of neurons actually are they help regulate reproduction and temperature.

所以当我们进入围绝经期和绝经期、雌激素水平降低时，雌激素实际上会调控这些神经元。

So what happens when we have low estrogen during perimenopause and menopause, estrogen actually regulates these.

因此，当体内没有雌激素时，这些 KINDY 神经元——顺便说一句，我超爱这个名字——就会过度活跃。

So when we don't have any estrogen there, these candy neurons, I love the name by the way, these candy neurons, they're hyperactive.

好的。

Okay.

好的。

Okay.

他们不知道发生了什么。

They don't know what's going on.

没有雌激素了。

There's no one estrogen's not there.

他们寻找雌激素，却发现没有它来调控。

They're looking and estrogen's not there to control it.

对吧？

Right?

所以这些神经元、这些集群开始失控。

So these neurons, these clusters start going crazy.

它们想：哦，这就是我们出现潮热的原因。

They go, oh, and this is why we get hot flashes.

所以，这是关于为什么我们无法正确调节体温的假设之一。

So this is one of the, you know, one of the the hypothesis as to why we can't regulate temperature correctly.

当我们出现潮热时，会有一股血液涌出，因为顺便说一下，大脑的葡萄糖代谢也起着作用。

And when we get hot flashes, we get a a rush of blood because your brain is also by the way, glucose metabolism also plays a role.

嗯。

Mhmm.

明白吗？

Okay?

当大脑缺乏葡萄糖且不知所措时，会发生许多事情。

When the brain is starved of glucose and it doesn't know what to do, many things happen.

知道吗？

K?

我们知道身体会开始分解脂肪，但就潮热而言，我们会感到血液涌遍全身，因为大脑在感知：天啊。

We know that we start to catalyze fats, but in relation to hot flashes, we get a rush of blood that goes through our body because the brain is sensing, oh my god.

我快饿死了。

I'm starving.

我不知道该怎么办。

I don't know what to do.

所以我们会出现这种血流涌动，最终表现为潮热。

So we get this rush of blood which ends up becoming a hot flash.

好的。

Okay.

fMRI研究显示，在潮热发生前，脑干会活跃起来。

They showed on fMRI studies that the brainstem lights up just before a hot flash happens.

脑干负责该区域的体温调节，同时它也控制着呼吸和睡眠。

The brainstem is responsible in that area for temperature control regulation, but also this is where it controls breathing and sleep.

所以这很可能解释了为什么很多女性在睡眠中会出现潮热。

So this is probably why a lot of women are having these hot flashes during sleep.

然后我们就会出现睡眠中断，而问题的连锁反应正是从这里开始的。

Then we get this sleep disruption, which is where the cascade of problems happen.

是的。

Yeah.

然后跟我聊聊血清素、去甲肾上腺素，这些小小的化学物质

And then talk to me about serotonin, norepinephrine, these these little chemicals that

它们会跳跃，你知道的，从一个神经元传到另一个神经元。

jump, you know, signals from neuron to neuron.

是的。

Yeah.

所以当我们的脑细胞彼此交流时，会使用一种叫做钠钾泵的机制。

So when our brain cells are communicating with one another, we use something called a sodium potassium pump.

但没错。

But yeah.

它会释放这些神经递质，它们只是化学物质，明白吗？负责许多功能，比如快乐——血清素和多巴胺，还有动机等神经调节作用。

So it releases these these neurotransmitters, which are just chemicals, okay, that are responsible for many things, happiness, you know, serotonin and dopamine, motivation to neuromodulator.

有趣的是，它们主要存在于两个区域，但最集中的是在额叶。

Funnily enough, they live in two areas, but most predominantly in the frontal lobe.

那么，额叶主要由什么组成呢？

And what's what's the frontal lobe predominantly filled with?

它们存在于雌激素受体所在的位置，以及海马体中。

They're out where our estrogen receptors are and also the hippocampus.

因此，当我们看到这些物质减少时，也会看到神经元之间沟通效率的下降。

So when we see a decline in that, we see a decline in the inefficiency of the neurons to communicate with one another.

好的。

Okay.

你能谈谈我们正在观察到的心理健康变化吗？

And can you talk a little bit about the mental health changes we're seeing?

我在临床中明显看到这一点。

I see this in clinic acutely.

正在开处SSRI类药物。

The SSRIs being prescribed.

在我的诊所里，你知道，数据也支持这一点。实际上，一些来自澳大利亚的优秀研究显示，在围绝经期使用激素替代疗法治疗新发的焦虑或抑郁，患者的改善情况远优于直接使用SSRI。

So in my clinic, you know, and the data holds this up, actually some great data coming out of Australia that looked at using HRT in perimenopause for new onset anxiety or depression and seeing how well those patients were doing much better than than putting them on an SSRI.

但大多数医生并不知道如何开具激素疗法处方，或者对此感到不自在，因为他们从未接受过相关培训。

But most doctors haven't learned how to prescribe hormone therapy or uncomfortable doing it because they were never taught.

而且，他们通常默认开大量的SSRI来治疗潮热。

And as a default, they are prescribing a lot of SSRIs to treat hot flashes.

是的。

Yeah.

希望我们能普及相关知识，提供更多更好的治疗选择。

Hopefully, we can get everybody educated and and get some better options out there.

但事实上，美国大约有10%的女性在40岁之前都在服用SSRI药物。

But the fact of the matter is about 10 of women in The US are on are getting their prescriptions filled for an SSRI up until about age 40.

嗯。

Mhmm.

而在围绝经期过渡阶段，这个比例翻了一倍。

And then across the perimenopause transition, that doubles.

是的。

Yes.

翻了一倍。

Doubles.

到了65岁，这个比例又上升了五个百分点。

And then at 65, it goes up another five percent.

当你提到，如果她们接受激素替代疗法，这种情况或许可以被替代或更好地监测。

When you're saying that it could be replaced or monitored better if maybe they got on hormone replacement therapy.

对于围绝经期新出现的精神健康问题，或者之前用药控制良好但突然变得难以管理的女性，添加或开始使用激素替代疗法（HRT），可能比加用第二种SSRI或重新开始用药更能帮助她们。

There is, at least for a new onset mental health change in perimenopause or someone who was previously well controlled on her medication and now suddenly is not manageable, adding in and, you know, starting on HRT or adding an HRT to that regimen will probably benefit her better than adding in a second SSRI or starting her to start.

我认为重要的是要理解，当大脑无法正常运作时，比如我们之前讨论过的结构性和功能性变化，以及白质病变，可能会引发一系列不同的问题。

I think what's important to understand is that when your brain doesn't function adequately the way that it's supposed to, meaning, like, the both structural and functional changes and, the white matter lesions that we discussed earlier, it can cause an array of different issues.

如果你的大脑不知道如何正常运作，它就会开始自己胡思乱想。

If your brain doesn't know how to function properly, it starts to think to itself.

你要从进化的角度来思考。

You gotta think evolutionarily.

明白吗？

Okay?

嗯，我正受到攻击。

Well, I'm under attack.

嗯嗯。

Mhmm.

交感神经系统失控。

Sympathetic nervous system out of control.

神经炎症，这实际上是你在身体里看到的炎症，但它发生在大脑中，开始使你的大脑发炎。

Neural inflammation, which is literally the inflammation that you see in your body, but it's in the brain, and it starts to inflame your brain.

明白吗？

K?

这正是导致抑郁样症状的原因。

And this is what's causing depressive like symptoms.

如果她们没有通过激素替代疗法或其他形式的治疗得到调节，可能会感到困惑。

And they can get be confused if they're not downregulated by hormone replacement therapy or other forms of therapy as well.

运动是一个很好的调节方式，顺便说一下。

Exercise is a great mediator, by the way.

肌酸是一种极好的调节剂，我们稍后会详细讲。

Creatine is a fantastic media, which we'll go into.

所以如果你不关注这个问题，你可能会被误诊为只是需要抗抑郁药，然后只是让你平静下来。

So if you're not taking care of that thing, yes, you could be mistaken to just have an SSRI, and let's just calm you down.

普通的抑郁。

Garden variety Yeah.

抑郁。

Depression.

我们回去睡觉吧。

Let's go back to sleep.

是的。

Yeah.

孩子们睡不着。

The girls are not sleeping.

我的病人根本睡不着。

Like like, my patients don't sleep.

所以这几乎不是普遍现象，但天啊，我想大约百分之七十的人都存在某种睡眠障碍。

And so they almost not universal, but, oh gosh, I would say seventy percent are coming in with some kind of a sleep disruption.

是的。

Yeah.

如果潮热影响了她们的睡眠，我们可以解决这个问题。

If it's hot flashes that are disrupting their sleep, we can fix that.

嗯。

Mhmm.

你知道吗？

You know?

但即使我们控制了她们的血管舒缩症状，女性仍然在挣扎。

But even if we have their vasomotor symptoms controlled, women are still struggling.

还是会有凌晨两点醒来的情况。

There's still that 2AM.

她们上床时似乎还好，但就是会在凌晨两点或三点醒来。

They're going to bed okay, it seems like, but they're having that 2AM, 3AM wake up.

是的。

Yeah.

而且这种情况是持续性的。

And it's it's consistent.

是的。

Yeah.

你知道吗？

You know?

每个人偶尔都会这样。

Everybody's gonna do that once in a while.

但你知道吗，能跟我详细说说，你认为为什么会发生这种情况吗？

But, you know, walk me through why do you think this is happening.

这很有趣，因为我确实见过很多女性患者被开阿米替林。

And that's interesting because I've actually seen a lot of female patients getting prescribed amitriptyline Mhmm.

你知道，用它来替代改善睡眠，我觉得这太荒谬了，因为这是一种三环类抗抑郁药。

You know, in replacement of poor sleep, which I think is crazy because it's a tricyclic antidepressant.

失眠的原因有很多，但通常情况下，你频繁醒来是因为褪黑素耗尽了。

And so insomnia is occurring for a number of different reasons, but what tends to happen is the reason why you're waking up more often is because you've run out of melatonin.

对吧？

Right?

这正是睡眠医学专家安德里亚·马特苏拉所说的。

And that is what Andrea Matsumura, who's a sleep medicine specialist, says.

是的。

Yeah.

所以你的大脑会把你唤醒，这可能是你的昼夜节律出现了紊乱。

So your brain wakes you up, and this could be a disruption in your circadian rhythm.

褪黑素去哪儿了？

Where did the melatonin go?

为什么我们会缺乏褪黑素呢？

Like, why why do we not have melatonin?

松果体功能紊乱了，它就是会把你唤醒。

The pineal gland is just disrupted, and it's just waking you up.

然后你就再也睡不着了。

And then what happens is you can't get back to sleep.

你会有思绪纷飞的情况。

You've got the racing thoughts.

另一个非常重要的原因是孕激素减少，而孕激素是激活GABA的。

And then we've got a really big one is because the loss of progesterone, which is activating GABA.

GABA是主要的抑制性神经递质。

And GABA is the chief inhibitory neurotransmitter.

因此，你常常会看到女性有两种主要的抱怨。

So oftentimes what you see is women have got two complaints.

我很难入睡。

I'm having trouble falling asleep.

是的。

Mhmm.

我很难保持睡眠。

I'm having trouble staying asleep.

明白吗？

Okay?

其中一个可能是体温调节问题。

One may be a temperature control problem.

另一个可能是思绪纷乱。

One may be racing thoughts.

如果夜间是思绪纷乱导致难以入睡，那没关系。

If it is the racing thoughts at night, I'm having trouble falling asleep, that is okay.

这跟孕酮有关。

It's progesterone.

我知道孕酮疗法有帮助，但γ-氨基丁酸也有用。

I know that progesterone therapy helps, but also gamma aminobutyric acid.

以补充剂形式摄入GABA也可能有帮助。

GABA in the form of a a supplement could help as well.

哦，太好了。

Oh, good.

是的。

Yeah.

我认为这正是认知行为

And I think this is where maybe cognitive behavioral

疗法或行为疗法可能有帮助的地方。

therapy behavioral therapy could help.

但让我们转向一个事实，即我们需要核心体温下降才能入睡并保持睡眠。

But let's go and switch to the fact that we actually need our core body temperature in order to fall asleep and stay asleep.

我们的核心体温需要下降至少两度。

Our core body temperature needs to drop at least two degrees.

很多

A lot of

女性并不了解这一点。

women don't understand this.

是的。

Yeah.

你知道，我们经常提到睡眠卫生这个词。

You know, we throw out the word sleep hygiene.

是的。

Yeah.

就像吃糖果一样，人人都能做到。

Like, it's candy, and everybody can do it.

但这个真的很难。

But this this is hard.

对。

Yeah.

要降低你的核心体温？

To to drop your core body temperature?

哦，这非常难。

Oh, it's very hard.

所以我掌握了一些不同的方法。

And so I've got a number of different techniques.

但为了入睡，实际情况是你的身体可能会升高核心体温，从而让你醒来。

But in order to fall asleep so what what is happening is your body can be raising its core body temperature and waking you up.

所以发生的是我们的皮质醇水平会上升

So what happens is our cortisol rises

嗯。

Mhmm.

根据太阳的运行。

According to the sun.

好的。

Okay.

所以如果太阳——

So if the sun okay.

我们的核心体温会上升，而这才是真正让我们醒来的因素。

Our core body temperature rises, and that's what actually wakes us up.

皮质醇会在早晨让我们醒来。

Cortisol wakes us up in the morning.

但如果你在凌晨两点醒来，那我们就得思考，是皮质醇的问题吗？

If But you're waking up at 2AM, then we have to think, is it cortisol?

是交感神经系统被激活了吗？

Is it the activation of your sympathetic nervous system?

还是核心体温的问题？

Or is it core body temperature?

因为一旦你的身体感觉到变暖，就会醒过来。

Because the moment that your body senses that it's getting warmer, it'll wake you up.

很多女性晚上都会觉得特别热。

And a lot of women do struggle with getting hot at night.

为了降低体温，你可以做很多事。

So to cool the body down, there's many things you can do.

一个非常简单的技巧是晚上把脚伸到被子外面。

Really easy hack is having your feet outside of the sheets at night.

我以前无意识地就这样自我调节了。

I I was self regulating doing that without thinking.

一条腿伸在外面

That one leg out of

是的。

the Yes.

从被子外面伸出来。

Out of the cut.

比如，我会不自觉地这么做。

Like, I would do it without thinking.

我会醒过来，发现一条腿在外面。

I'd wake up, and one leg would be out

真的吗？

Really?

好吧。

Okay.

是的。

Yeah.

从床上伸出来。

Of the bed.

因为现在我们有了能自动降温的床垫。

Because now we have the mattress that cools automatically.

选择吧。

Choose.

一个温控床垫。

A temperature controlled mattress.

但不是每个人都能负担得起。

And not everyone can afford this.

所以不行。

So No.

而且你也不必这么做。

And you don't have to.

明白吗？

Okay?

有趣的是，睡前洗个热水澡会显著提高你的核心体温。

Funnily enough, having a hot shower prior to going to bed raises your core body temperature really high.