Inflammation, Limbic White Matter, and Symptoms After Repetitive Head Impacts in Retired Football Players

我是何塞·梅里诺，《神经病学》系列期刊的主编。

This is Jose Merino, editor in chief of the Neurology family of journals.

《神经病学》播客为神经科医生和其他临床医生提供实用信息，帮助他们更好地照顾患者。

The Neurology Podcast provides practical information to neurologists and other clinicians to help them provide better care for their patients.

感谢收听，祝您本周愉快。

Thanks for listening, and have a great week.

大家好，欢迎收听《神经病学》播客。

Hello, Neurology Podcast listeners.

我是亚历山大·门策。

This is Alexander Menze.

我任职于加利福尼亚州萨克拉门托的永久医疗集团。

I'm with the Permanente Medical Group Sacramento, California.

今天，我采访了来自佛罗里达大学临床与健康心理学系的布雷顿·阿斯肯。

Today, I'm interviewing Breton Asken with the Department of Clinical and Health Psychology at the University of Florida.

我们将讨论一篇发表在《神经病学》上的论文，题目是：重复性头部撞击的退役美式橄榄球运动员中，炎症、边缘系统白质微观结构与临床症状的关系。

We will be discussing a paper published in Neurology titled inflammation, limbic white matter microstructure and clinical symptoms and retired American football players with repetitive head impacts.

下午好，Breton。

Good afternoon, Breton.

感谢你今天参与我们的访谈。

Thank you for joining us today.

是的，下午好。

Yeah, good afternoon.

非常感谢邀请我参加。

Thanks so much for having me.

Breton，我们非常期待了解创伤性脑损伤、头部损伤对患者长期的影响。

Breton, we're really excited to learn about traumatic brain injury, head injury, and its impacts on our patients over the long term.

请跟我们的听众说说，这篇论文为什么能推动我们对橄榄球运动员反复头部撞击的理解。

Please tell our listeners why the information in this paper moves the chains on our understanding of repetitive head injury in football players.

现实情况是，我们对反复头部撞击的后果，无论是对美式橄榄球运动员还是其他高风险人群，仍然知之甚少，因此每取得一点进展都弥足珍贵。

The unfortunate reality is that we still have so much that we're learning about the implications of repetitive head impacts and whether that's from American football players or other high risk populations that it feels like every yard we're gaining in this is valuable.

在这项研究中，我们觉得第一步应该是把过去各自独立研究发现的线索串联起来。

And in this particular study, we essentially thought that a good way to move the chain in the first place would be start trying to link together what previously had been studied and shown but separately.

比如，记忆力减退是我们从那些出现认知衰退的前美式橄榄球运动员那里最常听到的主诉之一。

So memory difficulties, for example, are some of the most common complaints that we'll hear from former American football players that are experiencing cognitive decline.

影像学研究已经提示，这些与边缘系统相连的脑结构可能特别容易受到反复头部撞击的影响。

And imaging studies have been implicating these limbic connected structures as maybe being especially vulnerable to the effects of repetitive head impacts.

近年来，研究还发现反复头部撞击与炎症和免疫信号通路的变化有关，我们试图把这些线索整合起来。

And then more recently, there have been ties between these repetitive head impacts and alterations to inflammation and immune signaling pathways that we tried to put all this together.

多亏了波士顿大学主导的、已确诊的慢性创伤性脑病研究提供了极其丰富的数据，再加上我在佛罗里达大学实验室里一位非常出色的研究生奥利维亚·埃曼纽尔的细致工作——她是这篇论文的第一作者——我们才开始能指出，这些原本各自独立的研究线索，正在逐渐连成一体。

And thanks in large part to the really rich data available through this diagnosed CTE study that's been led out of Boston University and a lot of careful and meticulous efforts from a very talented graduate student in my lab at UF, Olivia Emanuel, she was the lead author, we started to be able to highlight that these individual lines of research are starting to maybe get connected a little bit more.

我们发现，炎症程度越高（我们通过血浆和脑脊液两种方式测量），边缘系统白质的微观结构损伤就越严重，而这种损伤又与记忆力下降直接相关。

So we showed that more inflammation, which we measured both with plasma and CSF, was related to worse microstructure in limbic white matter in the brain, and that in turn was related to worse memory.

重要的是，这种关联只出现在本研究中的前橄榄球运动员身上。

And importantly, these were links that we only saw in the former football players in this study.

在健康对照组里，我们根本没有观察到这种模式。

We didn't see this in the healthy control sample.

因此，我们不认为这仅仅是衰老带来的普遍现象，而更可能是这些前运动员长期遭受头部撞击所导致的特异性后果。

And so we don't think this is just reflecting some general phenomenon of aging per se, but might actually be something related to the head impact exposure that these former football players have.

所以，如果我理解得没错，布雷顿，你们在记忆方面发现了临床影响。

So if I'm hearing you correctly, Breton, we had clinical impact on memory.

你们把这和脑脊液生物标志物以及影像学检查联系起来了。

You tied it in with CSF biomarkers and radiographic imaging.

这样概括大致没错吧？

Does that sum it up approximately?

是的。

Yeah.

我觉得我们当时在试图构建一个由这三者组成的思维模型。

I think we had sort of a mental triangle of these things that we were trying to relate to each other.

我们推测，这种反复撞击可能长期引发炎症反应的变化，进而导致大脑出现某种改变，最终在临床上表现为记忆和执行功能障碍。

What we hypothesize as being the steps that might occur here, where this exposure might trigger something different chronically about inflammation, which would then lead to some change in the brain, which would then lead to some change clinically, like memory and executive dysfunction on cognitive testing.

你总结得完全正确。

So you've got that right.

很好。

Great.

谢谢你，布雷顿。

Thank you, Breton.

在我们深入讨论这篇论文的具体发现之前，别以为这是本期播客最后一个足球相关的双关语了。

So before we kick off on the details of this paper's findings, and no, that's not gonna be the last football pun of this podcast.

你能简单说明一下创伤性脑病综合征和慢性创伤性脑病（CTE）之间的区别吗？

But could you please give a brief rundown on the distinction between traumatic encephalopathy syndrome and chronic traumatic encephalopathy or CTE?

TES里的这个‘s’代表‘综合征’，正如你所说，这个字母承载了整个缩写的全部含义。

So the s in TES, that stands for syndrome, like you said, that letter is doing all the heavy lifting for this acronym.

TES是一个研究框架，以临床表现为依据，比如认知变化、神经行为变化，以及个体既往头部创伤的暴露程度。

So TES is a research framework that's anchored to clinical features like cognitive changes, neurobehavioral changes, as well as the extent of someone's prior head trauma exposure.

TES框架的目标是帮助我们预测谁可能患有慢性创伤性脑病（CTE）。

And the goal of the TES framework is to help us predict who has chronic traumatic encephalopathy or CTE.

CTE是一种神经退行性疾病。

CTE is a neurodegenerative disease.

它是由大脑中异常tau蛋白的特定类型和分布所定义的。

This is something defined by the specific type and distribution of abnormal tau that's accumulating in the brain.

这一点在TES和CTE之间非常重要，因为它呼应了阿尔茨海默病及相关痴呆研究领域越来越重视的一个观点：疾病的症状必须与导致这些症状的大脑实际病变区分开来。

And this is a really important distinction between TES and CTE because it aligns with what is becoming increasingly important in the broader field of Alzheimer's disease and related dementias where it's abundantly clear that symptoms of a disease need to be conceptually separated from the actual brain abnormalities leading to them.

很少有哪种症状组合或综合征能同时对单一疾病具有高度敏感性和特异性。

There are just so few examples of a particular set of symptoms or a syndrome that is both highly sensitive and specific to any single disease.

同一种疾病往往表现出非常广泛的不同临床类型。

And any single disease can present with a very broad spectrum of different clinical phenotypes.

TES和CTE也不例外。

And TES and CTE are no different.

有些人可能符合TES的研究标准，但并没有CTE，或者不只有CTE。

People can meet the research criteria for TES but not have CTE or not only have CTE.

也有些人患有CTE，却不符合TES的研究标准。

And there are people with CTE who are not gonna meet the TES research criteria.

正如我们在其他神经退行性疾病中所学到的——这很大程度上得益于针对特定疾病的生物标志物研发，以及越来越多在生前接受过全面评估的脑捐赠者——现在可以很清楚地看到，单靠症状来预测疾病或其根本病因，往往效果不佳。

And so as we've learned from other degenerative diseases, thanks in a lot of parts to the disease specific biomarkers that are being developed and a growing number of brain donors who were evaluated very extensively during life, it's pretty clear at this point that symptoms alone tend to be a suboptimal predictor of the disease or the diseases that cause them.

所以，TES主要捕捉的是症状表现，而CTE反映的才是大脑中实际发生的神经退行性病变。

So that's one of the important distinctions between TES capturing the symptoms, whereas CTE reflects the actual neurodegenerative disease that might be happening in the brain.

没错，我之前参加过一个关于TES和CTE的播客，当时就强调过，临床上我们绝对不能诊断了TES，然后回头告诉病人他们得了CTE。

Exactly, and so I'd been involved in a previous podcast on TES and CTE and saying that we clinically absolutely shouldn't be diagnosing TES and then turning around and telling the patients that they have CTE.

所以对我们临床医生来说，最重要的是别对TES的诊断太过兴奋。

And so that's really important for us clinicians is not to get too enthusiastic about the TES diagnosis.

当然，这些症状确实是我们需要帮助患者应对的，但不能过于激动，就把他们归到一类，直接告诉他们得了CTE。

Of course, those are the real symptoms that we need to help our patients with, but not getting overly enthusiastic, and then putting them in the bucket and telling these people that they have CTE.

这其实也符合我们对其他神经退行性疾病的看法。

This is something that aligns with how we're thinking about other degenerative diseases as well.

很多人正在调整自己与患者沟通的方式，更谨慎地讨论他们出现的症状，以及仅凭这些症状到底能做出多可靠的预测。

And a lot of people are updating their own ways they go about communicating with patients more generally about the symptoms they're experiencing and how much we can really predict based on those symptoms alone.

经典的例子是，一位老年人因为记忆力减退来看诊。

The classic example is the older adult who comes into a clinic with memory trouble.

症状是逐渐加重的。

It's progressive.

过去，医生一看到这种情况，马上就会认定这八成是阿尔茨海默病。

And historically, there was a pretty immediate jump to we can assume pretty safely that you have Alzheimer's disease.

但这些年我们逐渐明白，导致记忆力逐渐衰退的原因其实有很多。

And then as we've learned over the years, well, lots of things can lead to progressive memory decline.

而且阿尔茨海默病也并不总是以进行性记忆力减退为表现。

And Alzheimer's disease does not always present with progressive memory decline.

借鉴其他疾病的经验，我们在处理TSE和CTE时也可以采用类似的思路。

By following what we've learned from these other diseases, it'll be a very similar framework to follow for TES and CTE.

我也希望临床医生能像你刚才提到的那样，用更细致的方式向患者解释这些情况。

And I'm hoping that clinicians can also, as you just alluded to, phrase things to their patients in a way that also captures that nuance.

说得对。

Precisely.

研究人员和医生一直在努力寻找在世时准确诊断CTE的方法。

So researchers and clinicians have been trying to tackle ways to accurately diagnose CTE in the living.

这项研究对我们理解反复头部外伤带来了哪些关键启示？

So what questions about repetitive head injury does this study answer for us?

目前已有相当充分的数据表明，如果一个人曾长期遭受反复性头部撞击，日后患痴呆的风险会显著增加。

So at this point, there is pretty strong data suggesting that if you have this prior repetitive head impact exposure, RHI, it's gonna increase your risk for dementia later in life.

但从反复头部撞击到痴呆之间的机制，却远没有那么简单。

But how we get from RHI exposure to dementia is far less straightforward.

作为一种特定疾病，CTE 现在已经比较明确，能够和其他与tau蛋白相关的疾病区分开来。

So as a specific disease, the CTE is also now relatively well delineated and distinguished from other tau related diseases.

可能有些神经病理学家会提出不同意见，但确实有清晰的诊断标准能把它和其他疾病区分开。

You might get some pushback from some neuropathologists on that, but there are clear diagnostic criteria that help separate it from other diseases.

但真正复杂的是，并不是所有经历过反复头部撞击的人，哪怕撞击很严重，都会发展成 CTE。

But where this gets really complicated is that not everyone with RHI, even if it's extensive, is going to get CTE.

而且反复头部撞击似乎也会增加其他神经退行性疾病的风险。

And RHI also seems to be a risk factor for other neurodegenerative diseases.

因此，在我们的研究中，其实很难对 CTE 做出明确结论，因为我们并不清楚这些前橄榄球运动员中有多少人，甚至有没有人真正患有 CTE。

And so with our study, we actually can't say all that much about CTE specifically because we don't know if or how many of the former football players in this study have CTE.

我们也不能忽视这项研究本身的局限性——它本质上是一项横断面相关性研究。

And we also can't ignore the limitations that come with a cross sectional correlational study, which is what this was.

但我认为，我们正在逐步厘清那些与反复头部撞击相关的生物学通路和最易受损的脑区，这些可能为 CTE 或其他退行性疾病的发生和扩散创造了条件，最终导致一部分有此类撞击史的人出现认知或行为上的渐进性变化。

But I do think we are starting to hone the biological pathways, the brain structures that are most vulnerable to this RHI exposure that might be helping to set the stage for diseases like CTE or other degenerative diseases to develop and spread, and then ultimately leading to progressive changes in cognition or behavior for at least a subset of people who have that RHI exposure.

我们把这些都看作是开发更精准诊断方法的必要步骤，也希望未来能发展出有效的治疗手段，来应对RHI带来的影响。

And we look at this as all just being the necessary steps in developing better diagnostics, and hopefully down the road therapeutics that can help to combat the effects of RHI exposure.

您能详细说说这项研究中使用的不同生物标志物，以及所采用的放射影像或弥散张量成像技术吗？

Could you elaborate on the different biomarkers that were used in the study and the radiographic imaging or diffusion tensor imaging that was used in the study?

再给我们多讲一点这方面的内容吧。

Just tell us a little bit more about that.

这些其实是我们用来反映个体体内生物学变化的间接指标。

These were essentially our proxies for biological alterations in these individuals.

我们研究的体液生物标志物，既来自血液，也来自脑脊液。

So the fluid biomarkers that we studied were obtained both from plasma and cerebrospinal fluid.

在这项研究中，我们特意聚焦了几种与炎症相关的关键蛋白。

And we purposely focused on a couple of key inflammation related proteins for this study.

它们分别是白细胞介素6、肿瘤坏死因子α，以及胶质纤维酸性蛋白（GFAP）。

Those were IL six, TNF alpha, and glial fibrillary acidic protein or GFAP.

作为体液标志物，这些指标能更动态地反映潜在的、正在活跃或持续的疾病过程。

And as fluid markers, these really capture more of a dynamic indication of a potentially active or ongoing disease related process.

我们用的成像技术，也就是DTI，它捕捉的信息方式不太一样。

The imaging, the DTI that we used, those capture things a little bit differently.

这些指标反映的是大脑白质内部的微观结构变化。

These are measures of microstructure changes within the white matter of the brain.

我们特别关注了与边缘系统关键结构相连的白质纤维束。

We focused on white matter tracts that were connected to key limbic system structures.

我们把DTI的指标，比如分数各向异性FA和平均扩散率MD，看作是对大脑当前结构状态的一个快照，反映的是到那时为止累积的所有与疾病相关的改变。

And we think of these DTI measures like fractional anisotropy or FA and mean diffusivity or MD as really being more of a snapshot of the current state of the brain structure reflecting whatever cumulative burden of disease related changes have happened up to that point.

当然，这些指标完全独立于症状、认知测试和自我报告量表，这再次强调了生物标志物与临床症状标志物之间的关键区别，我们最终希望把它们整合起来，做出合理的解释。

And these, of course, are all completely independent of symptoms and cognitive testing and self report scales, getting back again to that important distinction between the biological disease related markers from more of the clinical symptom related markers that we then hopefully will integrate and make sense of.

但我们特意选择了这些标志物，因为其他研究已经提示炎症可能起着重要作用。

But we purposely tried to focus on these markers that were based on some other findings that inflammation is something that might be important.

尤其是边缘系统结构和大脑白质的变化，似乎对这种暴露特别敏感。

And then in particular, limbic system structures and white matter changes in the brain could be something that seem especially vulnerable to this exposure.

当我的病人问我关于DTI或扩散张量成像时，我会告诉他们，这项诊断技术目前还不适合用于临床常规。

When my patients ask me about DTI or diffusion tensor imaging, I tell them that this diagnostic technology is not really ready for prime time clinical use.

您的研究和对分数各向异性（FA）与平均扩散率（MD）的了解，是否表明我们现在已经有了一种临床上切实可用的工具，还是说这仍然主要停留在研究阶段？

Does your work and knowledge of fractional anisotropy or FA and the mean diffusivity suggest that we currently have a valuable tool clinically right now, or is this something that's still mainly in the research realm?

就FA和MD这些指标而言，我仍然同意您的看法。

When it comes specifically to metrics like FA and MD, I still agree with you.

公平地说，扩散成像能帮上忙的可不止这些指标，但就DTI本身而言，在研究领域里，FA和MD确实是最常被关注的指标。

And to be fair, those are not the only thing that, broadly speaking, diffusion related imaging might help you with, but with DTI in particular and in the research space, these have been very popular to study.

但我们还没找到FA或MD变化的明确模式或特征，能清楚区分这些变化是由哪种疾病引起的。

But we don't have a clear pattern or a signature of FA or MD changes that give us some specific signal that these changes are due to one disease versus another.

这其实也是结构成像普遍存在的局限——多种疾病可能影响重叠的脑区，而这些成像方式本身并没有特异性到能锁定某种特定疾病。

And that's really a limitation of structural imaging in general because multiple diseases can affect overlapping brain structures, and there isn't something disease specific about those modalities.

我相信这些指标在研究层面非常有价值，能帮助我们理解从反复头部撞击到多年后发展为痴呆之间，大脑发生了哪些生物学变化，但它们在个体层面用于诊断，比如判断慢性创伤性脑病（CTE），目前证据还远远不够充分。

I do believe that these are very valuable research tools for understanding the types of biological changes that might take someone from RHI exposure to dementia many years later, but their value at an individual level or informing a diagnosis like CTE is certainly not as well established.

关于生物标志物，您有没有发现记忆障碍或功能衰退的进展，和您所观察和使用的生物标志物之间有非常明确的关联？

Similarly with the biomarkers, did you find anything that was very clear associated between the memory or the progression of functional problems in the patients and the biomarkers that you saw and used?

是的。

Yeah.

有趣的是，我们重点关注了这三个方面：炎症的液体标志物、白质变化的影像标志物，以及认知结果。我们发现炎症与边缘系统白质之间存在关联，而边缘系统白质又与认知变化——尤其是记忆力——相关，但炎症液体标志物与认知变化之间并没有直接关联。

Interestingly, these three components we focused on between the fluid markers of inflammation, the imaging marker of white matter change, and then the cognitive outcomes, we saw the association of the inflammation with the limbic white matter, and then we saw the association from limbic white matter to cognitive changes, in particular memory, we did not see the direct association between the fluid markers of inflammation and the cognitive changes.

这其中还有很多细节值得进一步梳理，比如这些环节究竟是如何一步步发生的。

There's a lot that we could potentially still try to unpack there in terms of what stepwise might be happening in those links.

但我们没有找到足够有力的证据，能支持我们急着去开发一种临床可用的炎症标志物检测方法，以便对疑似CTE的患者做出明确的诊疗调整。

But we didn't see strong enough findings that would suggest, for example, that we should be rushing to develop a clinically viable biomarker test for these inflammation markers so that we can make very clear and purposeful changes to the care or the diagnostics for people that we're working up for suspected CTE.

要改变临床常规实践，引入新的检测手段或生物标志物，需要非常充分的依据。

It takes a lot to change what you might do in a standard clinical practice with new and emerging tests or biomarkers.

但说实话，要实现这一点，你必须有明确的诊断价值或治疗指导意义，必须是真正能落地的工具。

But truthfully, for that to happen, you really need something that has clear diagnostic or treatment related value, something that can be actionable.

而目前来看，我还不确定这些基于体液的炎症标志物，或者DTI指标，是否已经成熟到足以影响个体患者的临床决策。

And right now, I don't know that we're there yet with these fluid based inflammation markers or these DTI metrics for altering how at an individual level you might change somebody's care.

是的。

Yeah.

这正是临床真正需要的方向。

And that's clinically where the demand is.

病人来看病时，虽然不一定这么说，但他们的表情分明觉得你掌握着所有这些高科技设备和诊断工具。

If patients that come in, they just you can just they may not say it in these words exactly, but they look at you like you have access to all this technology, all these diagnostic tools.

我真觉得对不起他们。

I feel terrible.

你告诉我，我为什么这么难受？给我找出原因来。

Tell me why I feel terrible, and show me why.

给我做个检查，做个检测，让我看看我的核磁共振，证明我每天为什么这么累，为什么老记不住事。

Give me an exam, give me a study, show me my MRI that says why I feel tired every day, why I can't remember stuff.

不管是年轻患者还是年长患者，都是这样。

And this is in young patients and old patients.

他们可能会把症状跟十年前的一次旧伤联系起来。

They may try to link it into some remote injury way back ten years ago.

根据脑外伤的研究数据，那些多年前受过严重脑损伤，甚至轻微脑震荡的人，有一项针对二战老兵的双胞胎研究发现，那些有双胞胎兄弟曾患过轻微脑震荡的，三十年、四十年后患痴呆的风险更高。

And what we know from the TBI data is that people who had severe brain injuries or even MTBIs years ago, there's a twin study that came out in veterans from World War two, and and the veterans who had the twin that had MTBI was more at risk for dementia thirty years later, forty years later.

这些发现真的很引人深思。作为医生，从临床角度看，我不会说这让人痛心，但现实是我们目前还无法把这些先进的诊断技术真正应用到每个人的个体治疗中。

And so these are some really fascinating things, and it's just it's very I wouldn't say it's heartbreaking on the clinical side as a physician, but we just don't have the ability to take these extremely advanced diagnostic tools and apply them to people's individual lives right now.

所以这项工作对临床来说特别重要，因为我们正在寻找答案，必须找到这些方法，才能真正帮到这些患者，给他们指明方向。

But that's why this work is so important for the clinical side, because we're looking for that, we need that so that we can help these patients out and give them, point them in the directions to go.

完全同意。

Agree completely.

我们在患者这边也都有类似的挫败感——他们带着一个看似简单的问题来找我们，可实际上背后复杂得多，而我们至今还在努力搞清楚。

We all share some of that frustration on the patient side of why do we still have so much that we're trying to figure out with arriving at what I'm sure they view as a simple question that they're bringing to the table, but on our end that we know is really quite complicated.

很多患者的生活质量要么在持续下滑，要么已经长期处于极其糟糕的状态，这种绝望感，医患双方都能深切感受到。

And the quality of life for a lot these individuals is clearly either deteriorating or has been in just an ecstatic bad state for long enough that there's a sense of desperation with a lot of these patients that is felt on both sides.

这一点毫无疑问。

There's no doubt about it.

这也正是推动当前大量研究的重要动力。

And certainly is motivating a lot of the ongoing research.

我还想明确一点，头部外伤或脑损伤这个概念涵盖的范围非常广。

And I wanna make maybe one clear distinction too that this idea of head trauma brain injury is a very broad umbrella.

有很多患者都属于这个范畴。

There are a lot of patients that fall into this category.

我认为，像你提到的这些遭受过创伤性脑损伤的患者，无论是被诊断为重度创伤性脑损伤、轻度创伤性脑损伤还是脑震荡，并且长期出现脑雾或其他持续不愈的症状，和我们这里研究的群体其实有重要区别。

And I do think there's an important difference between the patients who have sustained a TBI like the ones you're mentioning, whether it's diagnosed as a severe traumatic brain injury or an MTBI or a concussion, and they're experiencing persistent symptoms like brain fog or other changes that are just not getting better.

这些患者群体和我们研究的慢性创伤性脑病（CTE）高风险人群很不一样，因为我们研究的并不是那些受过脑损伤后始终未能康复的人。

Those are really in some ways different patient populations than those that we studied here that are at risk for CTE, mainly because we aren't really studying the people who had a TBI and never recovered from it.

这可能会引发一些争议，但单纯从创伤性脑损伤本身来看，它其实并不是慢性创伤性脑病这种特定神经退行性疾病的一个明确风险因素。

And this might also get a little bit controversial, but TBI in and of itself is actually not a very well established risk factor for CTE as a specific neurodegenerative disease.

我们这里研究的这些人，一生中因为从事美式橄榄球运动，积累了大量反复性的头部撞击。

The individuals here are people that they, over the course of their life, by virtue of the sport they play with American football, have accumulated extensive repetitive exposure.

这些撞击次数可能高达数百次甚至上千次，但大多数情况下并没有明显症状。

This can be on the order of hundreds to thousands of impacts, but most of these are asymptomatic.

他们并不是每次被撞到头都会出现头晕、恶心，或者能被诊断为损伤的表现。

They're not every single time getting hit in the head and experiencing dizziness, nausea, or something that could be diagnosed as an injury.

不过，这些无症状的撞击也和频繁发生的有症状损伤——比如脑震荡——交织在一起。

But they're, of course, also mixed in with symptomatic injuries like concussions that are happening frequently.

而很多年之后，才逐渐出现认知或行为上的进行性变化，这时候，对于我们这些研究衰老和神经退行性疾病的人来说，就会开始听到一些令人担忧的信号。

And then it's only many years later that there's this onset of progressive cognitive changes or behavioral changes where, you know, for someone who works in more of that aging and degenerative disease space, we start to hear the things that raise concern for a neurodegenerative disease.

这些人可能和那些刚受伤几个月到一两年、一直没好转、去TBI门诊就诊的患者很不一样。

And these might be people that are very different from those that are showing up in more of a TBI clinic where it's just been months or a year or two after an injury, and they're just not getting better.

也许这两类患者群体之间的重叠，比我们现在意识到的要多。

And there may be more overlap between these patient populations than we're understanding right now.

但我们要明确一点：这些年长的前美式橄榄球运动员，和那些试图把问题归因于多年前一次单一事件的研究对象，是完全不同的两类人——就像你提到的，那可能发生在几十年前，而我们想搞清楚的是，怎么就从那时一步步发展成了痴呆。

But just to draw that distinction between these aging former American football players from some of those other types of studies where it's trying to tie a lot back to some single index event that, like you said, may have happened years or decades before, and we're trying to figure out how do we get from there to dementia later on.

说实话，我在看边缘白质变化和认知功能之间的散点图和线性回归结果时，真的有点看不懂。

I must admit that when I was reviewing the scatterplots and linear regressions on the limbic white matter changes and then cognition, that I had a difficult time making sense of those results.

满纸都是点，三条线，有的方向一致，有的好像又不一致。

I saw a lot of dots all over the page and three lines, and they may have been going in the same direction or maybe not.

但就这些数据而言，回归分析里有没有发现真正有意义的结论？

But with that data, did you see meaningful findings in it through those regression analyses?

你能再明确说说，这些数据到底告诉我们了什么吗？

And could you just hammer down the points of what that data told us?

我们特意保留了这些展示每个数据点的图表，是因为这类临床数据本身就充满个体差异，散点图这名字起得真贴切——确实就是一堆散开的点。

One of the reasons we made sure to include those types of figures that showed each of those individual data points is it is really important to appreciate the realities of human clinical data like this where there is so much variability, and scatterplot is really a pretty good name for those plots.

一旦引入基于表现或自我报告的评估指标，比如认知测试，或者情绪和行为问卷。

The moment you introduce performance based or self report metrics, whether that's cognitive testing or mood and behavior surveys.

这些数据对我们了解现实生活中的功能状态至关重要。

These are among the most valuable data points we have for capturing real world functioning.

但当你试图用新技术或复杂的生物标志物来预测这些指标时，很快就会意识到有多难。

But get ready to be immediately humbled when you try to predict these things even with newer technologies or sophisticated biomarkers.

在我看来，最有意义的发现是，这种边缘白质微观结构与记忆力下降的关联，只出现在前橄榄球运动员身上。

And from my perspective, least, the more meaningful findings were when it came to how this limbic white matter microstructure was associated with worse memory was that we only saw it in the former football players.

这首先表明，这里确实存在某种重要信号，而不仅仅是年龄增长带来的影响；而且当我们聚焦于那些被认定为患神经退行性疾病（如CTE）风险最高的人群时，这种关联尤为明显。

That first and foremost gave us some indication there's some important signal here that is not just a function of getting older, but that the association was also strongest when we drilled down to the former American football players that were considered to be at the highest risk for a neurodegenerative disease like CTE.

这个群体在橄榄球运动员中年龄偏大，而且过去经历过最频繁、最严重的头部反复撞击。

And that's gonna be the subset that even within the football group is on the older side, also those that have the most extensive prior repetitive head impact exposure.

为此，我们有时会用一些很基础的指标，比如他们打了多少年美式橄榄球。

And for that, we use sometimes things as basic as just how many years did they play American football.

而那些认知障碍证据最明确的人，正是我们关注的重点。

And the people that have the most convincing evidence of cognitive impairment.

所以我们只在橄榄球运动员中观察到这一现象，而在那些最有可能正在经历神经退行性疾病的球员中，这个关联甚至更明显。

So the fact that we only saw it in the football players and then in the subset of football players that, if we had to guess, are probably the most likely to truly be dealing with a neurodegenerative disease right now, we saw it got even stronger.

对我来说，更重要的启示是，这些效应量其实并不惊人，现实就是如此。

That was a more important takeaway for me, I think, the realities of effect sizes that are not gonna blow anybody away.

就像你说的，散点图里，要准确预测某个人的具体情况依然很困难。

And like you said, scatter plots where any point estimate prediction for one person's going to still be challenging.

好的，布雷顿。

Okay, Breton.

谢谢你的分享。

Thank you for that.

咱们现在来总结一下，看看这篇论文能得出什么结论。

Let's huddle up here and see what conclusions we can make from this paper.

目前来看，这些发现对临床实践有实际帮助吗？还是说，我们只是需要记住这一点，不仅针对橄榄球运动员，也包括所有可能遭受过反复头部撞击的患者。

And right now, could this be useful clinically in practice, or is this something that we just need to be keeping in mind for our patients, not just our football players, but anybody who may be suffering from some form of repetitive head injury.

这两点可能都对，但每次做研究，我们都不得不一再强调：我们需要更多时间，更多数据。

Both of those things are probably true to some degree, but you hate to have to keep saying it over and over again with research studies that we need more time, we need more data.

有些事情本来就是这样。

Some of that is just that's the case.

这一点仍然成立。

That is still true.

不过，我认为真正值得关注的是，那些有重复性头部创伤史的人体内可能存在长期改变的炎症反应和不同的免疫信号。

I do, though, think that is this story around potentially this chronically altered inflammation, different immune signaling in these individuals with RHI exposure.

随着我们积累更多数据，情况逐渐明朗，我们确实可以开始思考：如何将干预措施或建议，锚定在那些能优化这些生理系统的日常生活方式上，针对这些高风险人群。

As we get more data on this and as that continues to unfold, I think it is reasonable to start thinking about how we could anchor whether it's interventions or recommendations for these at risk populations towards lifestyle activities that optimize these systems.

这些内容其实很多医生已经在提醒患者了，比如保持身体和大脑活跃，重视心脏健康。

These are hopefully things people are already telling their patients, the importance of being physically and mentally active, prioritizing heart health.

我们无法让这些患者回到过去，消除他们经历过的头部撞击。

We can't go back in time for any of these patients and remove the head impact exposure from their histories.

这会让很多人感到无助，甚至觉得一切都太晚了，伤害已经无法挽回。

And I do think for a lot of people that instills a sense of helplessness for them and hopelessness that the damage is done.

那我还能做些什么呢？

What am I to do?

我希望，随着我们对这种暴露如何导致痴呆的理解逐渐加深，尤其是慢性炎症变化或大脑白质微观结构可能扮演的角色，我们能更谨慎、更准确地传达：这并不是说只要经历过这种暴露，就注定会得痴呆。事实上，保持这些健康的生活方式，对维护大脑整体健康依然有显著益处，能帮助延缓大脑衰老。

And I would hope that by starting to get maybe a better understanding of how we're getting from that exposure to dementia and if there is some role that chronically altered inflammation or these white matter microstructures in the brain might be playing, that we can be a little more careful and precise by explaining that this is not some predetermined path to dementia that occurs just because you've had this exposure, and that there is still absolutely a benefit to these types of activities in general brain health practices that can help protect their brain as they get older.

很多道理其实并不复杂，但我发现，有些患者如果能明白为什么这些做法可能对他们有帮助，就会更有动力去行动。稍微多一点背后的解释，往往就能推动他们迈出第一步。

And a lot of it's not rocket science, but I do get a sense from some patients that it can help if that recommendation is tied to some understanding of why we think it might be helping them, if they need just a little bit more motivation to start engaging with some of these activities.

当然，说起来容易，做起来难。

And granted, it's often easier said than done.

人们不总是能坚持理想的生活方式，原因有很多。

There's a lot of reasons people don't always engage in perfect lifestyle activities.

但至少，我希望这类研究能强化临床实践中的某些建议，给那些面临更高神经退行性疾病风险的人带来一点希望——哪怕现实是，他们确实面临患CTE等疾病的风险。

But at a minimum, I would hope that studies like this can help reinforce aspects of clinical practice and recommendations that can give some hope for people, even if the reality is that they're dealing with being at increased risk for a neurodegenerative disease like CTE.

非常好。

Fantastic.

让我们回到研究本身，谈谈这个话题。

Let's circle this back to our research world here.

那我们该如何继续推进这方面的研究？

So how do we keep driving on the research of this topic?

下一档进攻线在哪儿？

Where's the next first down?

其实我们已经在做了。

We've already started actually in some ways.

这个诊断CTE的研究项目，数据就是来自这项研究，几年前就已经结束了。

So this Diagnose CTE research project where this data came from, that study wrapped up a couple of years ago.

但接下来的跟进项目，我简单称之为‘诊断CTE二期’，现在已经启动，正在招募参与者。

But the follow-up initiative that I'm just gonna call it Diagnose CTE two for simplicity is already underway, currently enrolling.

我们现在正在长期追踪最初那批确诊CTE的受试者。

We are longitudinally now following the people from that original diagnosed CTE cohort.

我们还新增了一个阿尔茨海默病对照组，以便更清楚地分辨，这些发现到底是特属于有头部撞击史且疑似CTE的人群，还是说只是神经退行性疾病的普遍现象。

We've expanded to include an Alzheimer's disease comparison group to help us better understand what if any of these findings are actually specific to people with prior RHI and suspected CTE versus maybe a general phenomenon of degenerative diseases.

无论是‘诊断CTE一期’还是现在的‘二期’，我们都保存了血液和脑脊液样本，这样一旦出现新的生物标志物，就能迅速测试和验证。

And with both of these, both the diagnose one and now diagnose two studies, they've involved banking samples of blood and CSF that enable us to test newly emerging biomarkers, validate new biomarkers very quickly as they come out.

这样我们就能更快地找到更准确、更针对CTE的生物标志物。

And so that's gonna hopefully then get us closer to a more accurate and CTE specific biomarker.

我本该在一开始就说这一点的。

And I should have said this at the beginning.

我对这项研究的参与者们的贡献怎么强调都不为过。

I can't say enough about the contributions of the participants in this study.

我接触过很多种神经退行性疾病的群体。

I work with a lot of different neurodegenerative disease populations.

他们每个人都非常愿意参与，这一点非常可贵。

They all bring a lot to the table in terms of their willingness to participate.

在我看来，这些前美式橄榄球运动员所展现出的奉献精神是独一无二的——他们愿意为下一代运动员的安全尽一份力，希望能让这项对他们意义重大、也对许多人意义重大的运动继续安全地进行下去。

There is, in my mind, something that's truly unique when it comes to these former American football players and what they're willing to do to help the next generation of athletes stay as safe as possible, to try to maintain a safe way to go about playing this game that meant so much to them and they know means a lot to other people.

除了已经为研究做出的贡献，许多参与者还同意捐赠大脑，这是最高程度的奉献，也能为我们提供最有价值的数据。

And beyond what they've already done for these studies, many of the people in the study have also agreed to donate their brains, which is the peak level of commitment and also the data that will give us the most helpful information.

因此，我们最终希望能获得尸检的金标准数据，来判断我们目前观察到的现象究竟是否与CTE有关，或是CTE与其他神经退行性疾病共同作用的结果，又或是完全不同的原因。

So we expect to eventually have the gold standard autopsy data to figure out if or how much of what we're seeing in this current cohort is actually related to CTE or some combination of CTE with other neurodegenerative diseases or something else entirely.

这其中有一部分是长远的布局，因为我们已经能够持续追踪这个群体，并且现在顺利开展了CTE诊断二期研究。

So there is a piece of this that's the long game because we've been able to follow-up with this cohort and have this diagnosed CTUs two study now going.

再加上神经退行性疾病领域中生物标志物的迅猛发展，我相信未来几年我们就能得到一些答案，而过去我们一直缺乏相应的工具和资源。

That in combination with just the very rapidly emerging world of biomarkers in the neurodegenerative disease space, I'm optimistic that we'll have some answers in the next few years that we haven't just had the tools or the resources to get to it up to this point.

是的。

Yeah.

我们一定要记住那些亲身经历这些状况、并为推动我们的研究付出巨大努力的人。

It's very important to remember the people that are involved and experiencing these things and the effort that they're putting in to helping us move forward with our knowledge.

这些信息太有用了，布雷顿。

This is great information, Breton.

非常感谢你今天与我们分享你的专业知识。

Thank you so much for sharing your knowledge with us today.

再次感谢你。

Thank you again.

我很享受这次对话，也非常感谢有机会能突出展示这项研究、这个群体以及所有参与者的贡献。

I enjoyed this, and we appreciate the ability to highlight this work and and this cohort and the all the participants involved.

我刚才与布雷顿·阿斯肯讨论了他的论文，题目是《重复性头部撞击退役美式橄榄球运动员的炎症、边缘区白质微观结构与临床症状》。

I've been speaking with Breton Asken about his paper titled inflammation, limbic white matter microstructure, and clinical symptoms in retired American football players with repetitive head impacts.

谢谢您，Breton。

Thank you, Breton.

谢谢。

Thank you.

我是您的播客编辑斯泰西·克拉迪。

This is Stacy Clardy, your podcast editor.

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