Center for Translational Neuromedicine, University of Copenhagen, Copenhagen N, Denmark, 2200.
Department of Anesthesiology, Yale School of Medicine, Yale University, New Haven, Connecticut 06520-8051.
J Neurosci. 2019 Aug 7;39(32):6365-6377. doi: 10.1523/JNEUROSCI.1974-18.2019. Epub 2019 Jun 17.
The glymphatic system is a brainwide CSF transport system that uses the perivascular space for fast inflow of CSF. Arterial pulsations are a major driver of glymphatic CSF inflow, and hypertension that causes vascular pathologies, such as arterial stiffening and perivascular alterations, may impede the inflow. We used dynamic contrast-enhanced MRI to assess the effect of hypertension on glymphatic transport kinetics in male young and adult spontaneously hypertensive (SHR) rats compared with age-matched normotensive Wistar-Kyoto rats (WKY). We anesthetized the rats with dexmedetomidine/isoflurane and infused paramagnetic contrast (Gd-DOTA) into the cisterna magna during dynamic contrast-enhanced MRI to quantify glymphatic transport kinetics. Structural MRI analysis showed that cerebroventricular volumes are larger and brain volumes significantly smaller in SHR compared with WKY rats, regardless of age. We observed ventricular reflux of Gd-DOTA in SHR rats only, indicating abnormal CSF flow dynamics secondary to innate hydrocephalus. One-tissue compartment analysis revealed impeded glymphatic transport of Gd-DOTA in SHR compared with WKY rats in both age groups, implying that glymphatic transport, including solute clearance from brain parenchyma, is impaired during evolving hypertension in young SHR, an effect that worsens in states of chronic hypertension. The study demonstrates the suppression of glymphatic clearance in SHR rats and thus offers new insight into the coexistence of hypertension and concomitant vascular pathologies in Alzheimer's disease. The study further highlights the importance of considering the distribution of tracers in the CSF compartment in the analysis of the glymphatic system. The glymphatic system contributes to the removal of amyloid β from the brain and is disrupted in Alzheimer's disease and aging. Using a rat model of hypertension, we measured gross CSF flow and tracked glymphatic influx and efflux rates with dynamic contrast-enhanced MRI, showing that glymphatic transport is compromised in both early and advanced stages of hypertension. The study provides a new perspective on the importance for brain metabolite and fluid homeostasis of maintaining healthy blood vessels, an increasingly pertinent issue in an aging population that in part may explain the link between vascular pathology and Alzheimer's disease.
糖质系统是一个脑内 CSF 转运系统，利用血管周围间隙进行 CSF 的快速流入。动脉搏动是糖质 CSF 流入的主要驱动力，而导致血管病变的高血压，如动脉僵硬和血管周围改变，可能会阻碍流入。我们使用动态对比增强 MRI 来评估高血压对年轻和成年自发性高血压（SHR）大鼠与年龄匹配的正常血压 Wistar-Kyoto 大鼠（WKY）之间糖质转运动力学的影响。我们用右美托咪定/异氟醚麻醉大鼠，并在动态对比增强 MRI 期间将顺磁对比剂（Gd-DOTA）输注到枕大池，以定量糖质转运动力学。结构 MRI 分析显示，无论年龄大小，脑室容积在 SHR 大鼠中均较大，而脑容积明显较小。我们仅在 SHR 大鼠中观察到 Gd-DOTA 的脑室反流，表明存在继发于先天脑积水的异常 CSF 流动动力学。单组织室分析显示，在两个年龄组中，与 WKY 大鼠相比，SHR 大鼠的 Gd-DOTA 糖质转运受到阻碍，这表明包括从脑实质清除溶质在内的糖质转运在年轻 SHR 的高血压进展过程中受损，这种效应在慢性高血压状态下恶化。该研究表明 SHR 大鼠的糖质清除受到抑制，从而为高血压和伴随的血管病变在阿尔茨海默病中的共存提供了新的见解。该研究进一步强调了在分析糖质系统时考虑 CSF 室中示踪剂分布的重要性。糖质系统有助于从大脑中清除淀粉样β，并且在阿尔茨海默病和衰老中受到破坏。我们使用高血压大鼠模型，通过动态对比增强 MRI 测量了总 CSF 流量，并跟踪了糖质流入和流出率，结果表明糖质转运在高血压的早期和晚期阶段都受到损害。该研究为维持健康血管对大脑代谢物和液体平衡的重要性提供了新的视角，这在部分上可能解释了血管病变与阿尔茨海默病之间的联系，因为在人口老龄化的背景下，这是一个日益重要的问题。
