Spreading edema after stroke The brain is enveloped in a cushion of cerebrospinal fluid (CSF), which normally provides protection and helps to remove metabolic waste. CSF transport has also recently been shown to play unexpected roles in neurodegeneration and sleep. Mestre et al. used multimodal in vivo imaging in rodents and found that, after a stroke, an abnormally large volume of CSF rushes into the brain, causing swelling (see the Perspective by Moss and Williams). This influx of CSF is caused by constrictions of arteries triggered by a well-known propagating chemical reaction-diffusion wave called spreading depolarization. CSF transport can thus play a role in brain swelling after stroke. Science, this issue p. eaax7171; see also p. 1195 In rodent models, the influx of cerebrospinal fluid along the glymphatic pathway swells the brain during ischemic stroke. INTRODUCTION Cerebrospinal fluid (CSF) covers and protects the brain from mechanical injury. CSF also flows along an interconnected network of perivascular spaces surrounding blood vessels and communicates with interstitial fluid permeating brain tissue, aiding in the removal of metabolic waste produced by cells. This glial cell–mediated lymphatic (glymphatic) function of CSF represents a continuous source of fluid and ions for the brain. When a cerebral artery is occluded, nearby brain tissue is abruptly deprived of blood flow, oxygen, and glucose. This process, known as acute ischemic stroke, is a leading cause of morbidity and mortality worldwide. After stroke, fluid accumulates in ischemic tissue, and the brain becomes edematous and begins to swell, a dangerous complication of the disease. In the first hours after occlusion, the degree of swelling correlates with the net gain of cations, primarily sodium, and this gain draws in fluid from surrounding sources. RATIONALE Because the brain is already encased by CSF, we asked if glymphatic flow could play a role in early edema formation. To test this, we evaluated CSF dynamics using in vivo magnetic resonance (MR) and multimodal optical imaging after occluding the middle cerebral artery in mice. Edema was assessed using diffusion-weighted MR, and edema fluid sources were labeled using radionuclides. Changes in the flow of CSF in perivascular spaces were explored using a network model of the mouse middle cerebral artery. Histology was used to evaluate edema formation in regions adjacent to CSF inflow routes in mouse and human autopsy tissue. RESULTS We found that within minutes of ischemic stroke, CSF flowed rapidly into brain tissue along perivascular spaces. Its entry coincided with the onset of swelling and increased brain water content. Radionuclides and multimodal imaging confirmed that CSF was the earliest contributor of both fluid and ions. Calcium imaging in transgenic mice expressing GCaMP7 in cortical neurons and astrocytes revealed that this process was initiated by spreading depolarizations that were triggered when tissue was deprived of blood flow. Diffusion-weighted MR imaging showed that this was the earliest phase of edema formation. This aberrant CSF inflow was found to be caused by spreading ischemia, the pathological constriction of cerebral blood vessels that follows spreading depolarizations. We present a network model that predicts that the space left unoccupied after vessels constrict would be filled by an inrush of CSF that nearly doubles flow speed. That prediction was confirmed experimentally using particle tracking velocimetry of CSF flow in live mice. Inflow depended on the aquaporin-4 water channel that is highly expressed by glial cells (astrocytes), which is a key contributor to glymphatic function. Postmortem examination of rodent and human brains showed increased fluid accumulation in tissue surrounding perivascular spaces and the cerebral ventricles compared with regions deep in the brain that were far from large CSF reservoirs. CONCLUSION Here, we demonstrate that CSF can provide a source of ischemic edema. Glymphatic inflow of CSF appears to be the primary initial event driving tissue swelling. This finding challenges our current understanding of edema formation after stroke and may provide a basis for treatment of acute ischemic stroke. Spreading depolarizations continue several days after stroke and are also present in many other neurological conditions, ranging from traumatic brain injury to migraine; therefore, it will be important to determine if spreading edema is also a feature of these diseases and whether CSF influx contributes to worsening at more delayed time points. It is also intriguing to speculate that abnormal CSF inflow could be a source of edema fluid in other types of chronic cerebrovascular disease, such as small-vessel disease characterized by enlarged perivascular spaces and transient accumulations of fluid in periventricular white matter. CSF influx is responsible for early tissue swelling after stroke. (Left) Spreading ischemia accelerates CSF inflow to the region deprived of blood flow. (Top right) Spreading ischemia constricts the cortical vessels, increasing the perivascular space and resulting in CSF inflow. (Bottom right) Histology of postmortem tissue shows fluid accumulation in the ischemic human brain (diffuse white empty space, right) that is not present in a control brain (left). ILLUSTRATION: DAN XUE Stroke affects millions each year. Poststroke brain edema predicts the severity of eventual stroke damage, yet our concept of how edema develops is incomplete and treatment options remain limited. In early stages, fluid accumulation occurs owing to a net gain of ions, widely thought to enter from the vascular compartment. Here, we used magnetic resonance imaging, radiolabeled tracers, and multiphoton imaging in rodents to show instead that cerebrospinal fluid surrounding the brain enters the tissue within minutes of an ischemic insult along perivascular flow channels. This process was initiated by ischemic spreading depolarizations along with subsequent vasoconstriction, which in turn enlarged the perivascular spaces and doubled glymphatic inflow speeds. Thus, our understanding of poststroke edema needs to be revised, and these findings could provide a conceptual basis for development of alternative treatment strategies.

中文翻译：

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脑脊液流入导致急性缺血组织肿胀

中风后水肿扩散 大脑被脑脊液 (CSF) 垫包裹，通常提供保护并有助于清除代谢废物。最近还显示脑脊液转运在神经变性和睡眠中发挥着意想不到的作用。梅斯特等人。在啮齿动物中使用多模式体内成像，发现中风后，异常大量的 CSF 涌入大脑，导致肿胀（参见 Moss 和 Williams 的观点）。这种 CSF 的流入是由众所周知的传播化学反应扩散波触发的动脉收缩引起的，称为扩散去极化。因此，脑脊液转运可以在中风后脑肿胀中发挥作用。科学，这个问题 p。eaax7171; 另见第 1195 在啮齿动物模型中，在缺血性中风期间，脑脊液沿淋巴管通路流入会使大脑肿胀。介绍 脑脊液 (CSF) 覆盖并保护大脑免受机械损伤。脑脊液还沿着血管周围的血管周围空间的互连网络流动，并与渗入脑组织的间质液连通，有助于清除细胞产生的代谢废物。脑脊液的这种神经胶质细胞介导的淋巴（淋巴）功能代表了大脑的液体和离子的持续来源。当脑动脉闭塞时，附近的脑组织会突然失去血流、氧气和葡萄糖。这一过程被称为急性缺血性中风，是全世界发病率和死亡率的主要原因。中风后，液体积聚在缺血组织中，大脑变得水肿并开始肿胀，这是疾病的危险并发症。在闭塞后的最初几个小时内，肿胀程度与阳离子（主要是钠）的净增加相关，并且这种增加会从周围来源吸收液体。 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 基本原理 因为大脑已经被 CSF 包裹，我们询问了淋巴流是否可以在早期水肿形成中发挥作用。为了测试这一点，我们在小鼠大脑中动脉闭塞后使用体内磁共振 (MR) 和多模态光学成像评估了脑脊液动力学。使用弥散加权 MR 评估水肿，使用放射性核素标记水肿流体源。使用小鼠大脑中动脉的网络模型探索了血管周围空间中脑脊液流动的变化。组织学用于评估小鼠和人体尸检组织中与 CSF 流入途径相邻区域的水肿形成。结果 我们发现，在缺血性中风的几分钟内，脑脊液沿着血管周围空间迅速流入脑组织。它的进入恰逢肿胀和脑水含量增加的开始。放射性核素和多模态成像证实，脑脊液是流体和离子的最早贡献者。在皮质神经元和星形胶质细胞中表达 GCaMP7 的转基因小鼠的钙成像显示，该过程是由扩散去极化引发的，当组织被剥夺血流时会触发去极化。弥散加权 MR 成像显示这是水肿形成的最早阶段。发现这种异常的脑脊液流入是由扩散的缺血引起的，扩散去极化后脑血管的病理性收缩。我们提出了一个网络模型，该模型预测血管收缩后未被占用的空间将被 CSF 涌入，几乎使流速增加一倍。使用活体小鼠脑脊液流动的粒子跟踪测速法通过实验证实了该预测。流入取决于由神经胶质细胞（星形胶质细胞）高度表达的水通道蛋白 4 水通道，这是对淋巴功能的关键贡献者。啮齿动物和人类大脑的尸检显示，与远离大型脑脊液储库的大脑深处区域相比，血管周围空间和脑室周围组织中的积液增加。结论 在这里，我们证明 CSF 可以提供缺血性水肿的来源。CSF 的 Glymphatic 流入似乎是驱动组织肿胀的主要初始事件。这一发现挑战了我们目前对中风后水肿形成的理解，并可能为急性缺血性中风的治疗提供基础。中风后数天，扩散性去极化会继续存在，并且还存在于许多其他神经系统疾病中，从创伤性脑损伤到偏头痛；因此，重要的是要确定扩散性水肿是否也是这些疾病的一个特征，以及脑脊液流入是否会在更延迟的时间点导致恶化。推测异常 CSF 流入可能是其他类型慢性脑血管疾病中水肿液的来源也很有趣，例如以血管周围间隙扩大和脑室周围白质中短暂积液为特征的小血管疾病。脑脊液流入是中风后早期组织肿胀的原因。（左）扩散缺血加速了脑脊液流入缺乏血流的区域。（右上）扩散缺血会收缩皮质血管，增加血管周围空间并导致脑脊液流入。（右下）死后组织的组织学显示，在对照大脑（左）中不存在的缺血性人脑（弥漫性白色空白空间，右）中的液体积聚。插图：丹雪中风每年影响数百万人。中风后脑水肿可预测最终中风损伤的严重程度，但我们对水肿如何发展的概念并不完整，治疗选择仍然有限。在早期阶段，液体积聚的发生是由于离子的净增益，普遍认为是从血管室进入。在这里，我们在啮齿动物中使用了磁共振成像、放射性标记示踪剂和多光子成像，以显示大脑周围的脑脊液在缺血性损伤的几分钟内沿着血管周围流动通道进入组织。这个过程是由缺血性扩散去极化以及随后的血管收缩引起的，这反过来扩大了血管周围空间并使淋巴管流入速度加倍。因此，我们对卒中后水肿的理解需要修正，这些发现可以为替代治疗策略的发展提供概念基础。放射性标记示踪剂和啮齿类动物的多光子成像显示，大脑周围的脑脊液在缺血性损伤的几分钟内沿着血管周围流动通道进入组织。这个过程是由缺血性扩散去极化以及随后的血管收缩引起的，这反过来扩大了血管周围空间并使淋巴管流入速度加倍。因此，我们对卒中后水肿的理解需要修正，这些发现可以为替代治疗策略的发展提供概念基础。放射性标记示踪剂和啮齿类动物的多光子成像显示，大脑周围的脑脊液在缺血性损伤的几分钟内沿着血管周围流动通道进入组织。这个过程是由缺血性扩散去极化以及随后的血管收缩引起的，这反过来扩大了血管周围空间并使淋巴管流入速度加倍。因此，我们对卒中后水肿的理解需要修正，这些发现可以为替代治疗策略的发展提供概念基础。这个过程是由缺血性扩散去极化以及随后的血管收缩引起的，这反过来扩大了血管周围空间并使淋巴管流入速度加倍。因此，我们对卒中后水肿的理解需要修正，这些发现可以为替代治疗策略的发展提供概念基础。这个过程是由缺血性扩散去极化以及随后的血管收缩引起的，这反过来扩大了血管周围空间并使淋巴管流入速度加倍。因此，我们对卒中后水肿的理解需要修正，这些发现可以为替代治疗策略的发展提供概念基础。