Long COVID brain fog may originate in a surprising place, say scientists

科学家表示，长新冠脑雾可能起源于一个令人惊讶的地方

https://www.npr.org/sections/goatsandsoda/2023/10/24/1207489490/long-covid-brain-fog-may-originate-in-a-surprising-place-say-scientists

科学家们发现了对 COVID-19 最令人烦恼的后遗症之一的可能解释：长期感染新冠病毒后出现的顽固神经系统症状，如脑雾、记忆力减退和疲劳。

当研究人员对长新冠患者的血液进行检查时，出现了第一个线索：正是血清素——具体来说，体内循环的神经递质的缺乏——引起了他们的注意。

他们的分析显示，这种化学物质的水平较低可以预测某人是否在感染后出现持续症状。

接下来，宾夕法尼亚大学的研究小组仔细地重现了可能消耗血清素并导致下游后果的一系列事件，这些后果可能与长新冠病毒的一些特征症状相符。

他们的研究结果发表在《细胞》杂志上，指出了一个有趣的假设，该假设从肠道蜿蜒穿过迷走神经，最终进入大脑。

该研究的资深作者、宾夕法尼亚大学微生物学助理教授 Christoph Thaiss 说：“基本上，我们可以通过这种导致血清素减少的途径来解释长新冠病毒的一些神经认知表现。”

这项工作给那些研究长新冠病毒的人留下了深刻的印象，这种疾病仍然没有经过验证的治疗方法，也没有被广泛接受的生物标志物可供医生用来诊断这种疾病。

该研究将有关该疾病潜在驱动因素的几条重要证据（病毒物质的持续存在、血液凝固和慢性炎症）编织在一起，并为可在人体中测试治疗方法的临床试验提供了可能的目标。

“这项研究给我留下了深刻的印象，”斯坦福大学神经学教授米歇尔·蒙杰博士说。“我认为他们做得很好，展示了这些变化的因果关系。”

耶鲁大学免疫学家 Akiko Iwasaki 表示，鉴于大部分工作是在小鼠身上完成的，对于长期感染新冠病毒的患者的影响仍需要在未来的研究中充分探讨，但结果讲述了一个“非常好的简单明了的故事”。

“每个参与这项研究的人现在都应该思考这种血清素途径，”岩崎说。

那么他们究竟发现了什么？

追踪脑雾的原因

考虑到血清素，研究人员试图从疾病过程的一开始就开始研究，主要利用小鼠实验来追踪其病程。

他们的预感是，“病毒持续存在”——长新冠病毒的一个主要嫌疑因素——可能是导致血清素消耗的原因。 多项研究表明，在最初的疾病过去很久之后，一些长期感染新冠病毒的患者可能会在身体的某些部位出现挥之不去的感染，有时被称为“病毒库”，这可能会导致他们出现一些症状。

资深作者 Maayan Levy 表示，他们通过检查长期感染新冠病毒的受试者的粪便中是否有病毒的遗传物质来寻找病毒持续存在的证据。

宾夕法尼亚大学微生物学助理教授 Levy 说：“在大约 30% 的患者中，我们可以在他们的胃肠道中发现病毒 RNA，因此我们尝试在小鼠身上建立模型。”

这些实验表明，慢性病毒感染（他们使用淋巴细胞脉络膜脑膜炎病毒作为 SARS-CoV-2 的替代品）也会导致血清素减少，而人体自身的免疫反应似乎是罪魁祸首。

这导致进一步的实验集中在一种称为 1 型干扰素的细胞因子上，揭示了这种信号蛋白以多种方式驱动炎症并干扰血液中的血清素水平。

肠道产生体内 90% 的血清素。 氨基酸色氨酸对于这项任务至关重要——它是血清素的前体，可以从我们吃的食物中被胃肠道吸收。 除此之外，肠道中的这种炎症反应实际上损害了色氨酸的吸收。

“如果色氨酸减少，血清素的产生就会减少，”泰斯说。 最重要的是，这些细胞因子还会导致储存血清素的血小板凝结，进一步减少循环中的血清素量。

与大脑的连接

在这里，侦探工作从肠道转移到迷走神经，迷走神经本质上就像大脑的身体监控系统一样，连接到胃肠道和许多其他器官。

利维说，他们发现血清素的减少会损害迷走神经和大脑之间的通讯，从而减少大脑中海马体区域的一些活动。

不过，有希望的是，宾夕法尼亚大学研究人员在小鼠身上记录的认知症状可能会被逆转。

泰斯说：“我们只需重新激活动物的迷走神经或恢复血清素信号，就可以让动物再次拥有完美的记忆。”他指的是他们对长期感染新冠病毒的小鼠模型进行的认知行为测试。

“我们不知道长期感染新冠病毒的人是否也会出现同样的情况。”

由于这项工作大部分是在小鼠身上完成的，因此对人类得出的结论存在局限性。Levy 指出，他们的数据无法证明病毒库是导致人类发生这些事件的原因，而且缺乏良好的长新冠病毒小鼠模型仍然阻碍了研究。

“为了向患者提出任何建议，我们需要进行一项控制良好的大型临床试验，”她说，“下一步显然是我们尝试一种干预措施，以增加血清素水平或刺激迷走神经 以其他方式或补充色氨酸。”

在他们的实验中，他们给小鼠注射了一种通用形式的百忧解（Prozac）——一类被称为 SSRI 【Selective serotonin reuptake inhibitor】的药物，通常用于治疗抑郁症并增加大脑中循环的血清素。

解开新冠病毒长期存在的复杂原因

斯坦福大学的 Monje 表示，这项研究提供了关于神经系统之外的免疫问题如何在COVID-19 后对大脑和其他功能产生深远影响的新见解。

“这不是整个谜题——也并不意味着是整个谜题——但它是它的一个非常重要的方面，”她说。

事实上，科学家并不指望找到一种机制，一旦被发现就能解决所有这些问题。

蒙杰说：“新冠病毒影响神经系统的方式有很多，但这些方式并不相互排斥。” “任何人都可能患有这些疾病的某种组合。”

例如，她的实验室发现，在小鼠中，肺部轻微的 COVID-19 感染会引发炎症级联反应，损害海马体神经元的产生。

长新冠“脑雾”综合症包含一系列症状，从记忆和注意力问题到信息处理速度，再到执行功能和疲劳。

Monje 说，对 COVID-19 影响的研究也揭示了大脑其他部位的神经生物学变化。 “它比海马体更广泛，但海马体肯定受到牵连。”

与所有长新冠病毒研究一样，挑战在于弄清楚这些发现如何适应我们对这种疾病不断变化的理解。

“长新冠肺炎是一种异质性疾病。有许多不同的表现，”纽约西奈山医学教授 Saurabh Mehandru 博士说。 “这是新颖、令人兴奋的数据。我认为这是重要的初步发现，需要进一步研究。”

Mehandru 说，鉴于 SARS-CoV-2 利用广泛表达于小肠表面的 ACE-2 受体，“色氨酸-血清素通路受到影响是有道理的”。

他说，“它在那里表达是因为它在氨基酸的吸收中发挥作用”，比如色氨酸。

但他表示，关于病毒在长新冠患者肠道内持续存在的问题，仍然存在许多悬而未决的问题。

因为这些细胞每三到五天更新一次，“对于任何在这一层持续活跃的东西，从定义上来说，这意味着存在一定程度的复制，”他说。 然而，目前还不清楚到底复制了什么。

多项研究发现不同组织中存在遗传物质和病毒蛋白的证据。 然而，他说，没有人真正从肠道组织中培养出这种病毒，这无疑是很难做到的。 “这些都是活跃且重要的科学领域。”

正如宾夕法尼亚大学的研究表明的那样，肠道中的慢性病毒感染可能会导致一些患者出现这些症状，但耶鲁大学的岩崎表示，长期感染新冠病毒的神经认知功能障碍可能是“许多不同因素的下游，包括循环炎症因子和自身抗体。 ”

岩崎说：“尽管这些点与动物模型和患者样本有很好的联系，但这种情况是否发生在患者身上以及有多少比例可能患有这种特定的病理学，仍然需要未来的研究。”他的研究发现，低水平 应激激素皮质醇的减少也与长新冠症状有关。

最终，这项研究可能无法解释长新冠病毒引起的所有神经系统症状——但这没关系，Monje 说。

“这并不是说我们必须将所有难题拼凑起来才能开始做出有意义的治疗改变，”她说。 “我认为值得进一步追求。”

Scientists have uncovered a possible explanation for one of COVID-19's most vexing legacies: the stubborn neurological symptoms of long COVID, such as brain fog, memory loss and fatigue. 

The first clue emerged when researchers scoured the blood of long COVID patients: It was serotonin – specifically, a lack of the neurotransmitter circulating in the body — that grabbed their attention.

Their analysis revealed that having low levels of that chemical predicted whether or not someone was suffering from persistent symptoms following an infection. 

Next, the team of researchers at the University of Pennsylvania carefully recreated the chain of events that might be depleting serotonin and causing downstream consequences that could line up with some of the symptoms characteristic of long COVID.

Their findings, published in the journal Cell, point to an intriguing hypothesis that winds its way from the gut up through the vagus nerve and ultimately into the brain. 

"Basically, we can explain some of the neurocognitive manifestations of long COVID through this pathway that leads to serotonin reduction," says Christoph Thaiss, a senior author on the study and an assistant professor of microbiology at the University of Pennsylvania. 

The work has made an impression on those studying long COVID, a condition that still has no validated treatment or widely accepted biomarker that doctors can use to diagnose the condition. 

The study weaves together several prominent lines of evidence on the potential drivers of the condition — the ongoing presence of viral material, blood clotting and chronic inflammation — and offers up possible targets for clinical trials that can test treatments in humans. 

"I'm impressed by the study," says Dr. Michelle Monje, a professor of neurology at Stanford University. "I think they did a beautiful job showing the causality of these changes."

Given that much of the work was done on mice, the implications for long COVID patients still need to be fully explored in future studies, but the results tell a "very nice linear story," says Akiko Iwasaki, an immunologist at Yale University.

"Everyone who's engaged in this research should now be thinking about this serotonin pathway," says Iwasaki. 

So what exactly did they find? 

Tracing the cause of brain fog

With serotonin on their minds, the researchers tried to start from the very beginning of the disease process, primarily using experiments on mice to trace its course. 

Their hunch was that "viral persistence" — a major suspect in long COVID — could underlie the depletion of serotonin. Multiple studies show that well after the initial illness passes, some long COVID patients may have a lingering infection in certain parts of the body, sometimes called a "viral reservoir," which could be driving some of their symptoms. 

Maayan Levy, a senior author, says they looked for evidence of viral persistence by checking the stool of their long COVID subjects for genetic material from the virus. 

"In about 30% of patients, we could find viral RNA in their gastrointestinal tract, so we took this and tried to model it in mice," says Levy, an assistant professor of microbiology at the University of Pennsylvania. 

Those experiments revealed that a chronic viral infection (they used lymphocytic choriomeningitis virus as a stand-in for SARS-CoV-2) also led to reductions in serotonin and that the body's own immune response seemed to be the culprit. 

This led to further experiments focused on a cytokine, called type 1 interferon, revealing that this signaling protein was driving inflammation and interfering with serotonin levels in the bloodstream in several ways. 

The gut produces 90% of serotonin in the body. The amino acid tryptophan is critical to this task — it's a precursor to serotonin and gets absorbed in the gastrointestinal tract from the food we eat. Except, this inflammatory response in the gut actually impaired the absorption of tryptophan. 

"If there's less tryptophan, there's less serotonin production," says Thaiss. On top of that, these cytokines also lead to clotting of blood platelets — which store serotonin — further reducing the amount of serotonin in circulation. 

The brain connection

Here, the detective work moved away from the gut to the vagus nerve, which essentially acts like the brain's monitoring system of the body and connects to the gastrointestinal tract and many other organs. 

Levy says they found this reduction in serotonin impairs communication between the vagus nerve and the brain, which then reduces some activity in a region of the brain known as the hippocampus. 

What's promising, though, is that the cognitive symptoms the Penn researchers documented in mice could be reversed. 

"We can make the animals remember perfectly again by just reactivating their vagus nerve or by restoring their serotonin signaling," says Thaiss, referring to a cognitive behavioral test they performed on their mouse models of long COVID. 

"Whether the exact same thing is true in individuals with long COVID is something we don't know." 

Because much of this work was done on mice, there are limitations to what conclusions can be drawn about humans. Levy points out that their data can't prove a viral reservoir is causing these events in humans and that a lack of good mouse models of long COVID still hampers research. 

"To make any recommendations for patients, we need to perform a large clinical trial that is well-controlled," she says, "The obvious next step would be for us to to try an intervention that will increase serotonin levels or stimulate the vagus nerve in other ways or [to] supplement tryptophan." 

In their experiment, they gave the mice a generic form of Prozac — a class of medication known as an SSRI that's typically prescribed for depression and increases circulating serotonin in the brain. 

Untangling the complex causes of long COVID

The research offers new insights into how immune problems outside of the nervous system can have far-reaching consequences on the brain and other functions in the aftermath of COVID-19, says Stanford's Monje. 

"It's not the whole puzzle — and it's not meant to be the whole puzzle — but it's a really important aspect of it," she says. 

Indeed, scientists don't expect to find a single mechanism that, once unearthed, will resolve all these problems. 

"There are many ways that COVID can influence the nervous system that are not mutually exclusive," says Monje. "Any individual might be suffering from some combination of those." 

For example, her lab has found that, in mice, a mild COVID-19 infection in the lungs sets off an inflammatory cascade that impairs neuron production in the hippocampus. 

The long COVID "brain fog" syndrome encompasses a constellation of symptoms, everything from problems with memory and attention to speed of information processing to executive function and fatigue. 

Monje says research on the effects of COVID-19 have revealed neurobiological changes elsewhere in the brain, too. "It's broader than just the hippocampus, but certainly the hippocampus has been implicated." 

As with all long COVID research, the challenge is figuring out how these findings fit into our ever-changing understanding of the disease. 

"Long COVID is a heterogeneous disorder. There are many different manifestations," says Dr. Saurabh Mehandru, a professor of medicine at Mount Sinai in New York. "It's novel, exciting data. I would consider this as important but initial findings which have to be further studied." 

Mehandru says "it makes sense the tryptophan-serotonin pathway is being affected" given that SARS-CoV-2 utilizes the ACE-2 receptor, which is widely expressed on the surface of the small intestines. 

"It's expressed there because it plays a role in absorption of amino acids" like tryptophan, he says. 

But he says there are still many open questions about this business of viral persistence in the gut of long COVID patients. 

Because these cells renew every three to five days, "for anything to be persistently active in this layer, it would by definition imply there's some level of replication," he says. It's not clear, however, exactly what's replicating.

Multiple studies have found evidence of genetic material and viral proteins in different tissues. Yet, no one has actually cultured the virus from intestinal tissue, which is admittedly difficult to do, he says. "These are active and important scientific areas of interest." 

While it's possible a chronic viral infection in the gut could be driving these symptoms in some patients, as the Penn study suggests, Yale's Iwasaki says the neurocognitive dysfunction in long COVID can be "downstream of many different things, including circulating inflammatory factors and autoantibodies." 

"Even though the dots are very well connected with animal models and patient samples, whether this is happening in patients and what proportion might be suffering from this particular pathology, that still requires future studies," says Iwasaki, whose research has found that low levels of the stress hormone cortisol are also associated with long COVID symptoms. 

Ultimately, this research may not explain all the neurological symptoms that surround long COVID — and that's okay, says Monje. 

"It's not that we have to put all the pieces of the puzzle together to begin to make meaningful therapeutic changes," she says. "I think it's worth further pursuing."