Heiss W D, Graf R, Wienhard K, Löttgen J, Saito R, Fujita T, Rosner G, Wagner R
Max-Planck-Institut für neurologische Forschung, Cologne, Germany.
J Cereb Blood Flow Metab. 1994 Nov;14(6):892-902. doi: 10.1038/jcbfm.1994.120.
Experimental models of focal cerebral ischemia have provided important data on early circulatory and biochemical changes, but typically their correspondence with metabolic and hemodynamic findings in stroke patients has been poor. To fill the gap between experimental studies at early time points and rather late clinical studies, we repeatedly measured CBF, CMRO2, oxygen extraction fraction (OEF), cerebral blood volume (CBV), and CMRglc in six cats before and up to 24 h after permanent middle cerebral artery (MCA) occlusion (MCAO), using the 15O steady state and [18F]fluorodeoxy-glucose methods and a high-resolution positron emission tomography (PET) scanner. Likewise, three sham-operated control cats were studied during the same period. Final infarct size was determined on serial histologic sections. In the areas of final glucose metabolic depression that were slightly larger than the histologic infarcts, mean CBF dropped to approximately 40% of control values immediately on arterial occlusion. If further decreased to < 20% during the course of the experiment. This progressive ischemia was most conspicuous in border zones. CMRO2 fell to a lesser degree (55%), eventually reaching approximately 25% of its control level. At early stages, OEF increased mainly in the center of ischemia. With time, areas of increased OEF moved from the center to the periphery of the MCA territory. Concurrently, progressive secondary decreases in OEF in conjunction with further reductions of CBF and CMRO2 indicated the development of central necrosis. The findings are highly suggestive of a dynamic penumbra. In five cats with complete MCA infarcts, CBF decreased and OEF increased in the contralateral hemisphere after 24 h, suggesting whole-brain damage. This effect may be explained by the widespread brain edema found histologically in addition to the nonspecific CBF reductions and OEF elevations observed also in the sham-operated controls after 1 day in the experimental condition. In one cat, cortical OEF increased only transiently. Normal CMRO2 and CMRglc were eventually restored, and the final infarct was small. This study demonstrates that acute regional pathophysiologic changes can be repeatedly assessed by multivariate PET in cats. Viable tissue can be detected up to several hours after MCA occlusion, and the transition of misery-perfused regions into necrosis or preserved tissue can be followed over time. The present results support the concept of a dynamic penumbra, in which for up to 24 h tissue damage spreads progressively from the center to the periphery of ischemia. Sequential high-resolution PET provides insight into the dynamics of regional pathophysiology and may thus further the development of rational therapeutic strategies.
局灶性脑缺血的实验模型已提供了有关早期循环和生化变化的重要数据，但通常它们与中风患者的代谢和血流动力学结果的对应性较差。为了填补早期实验研究与相当晚期临床研究之间的空白，我们在6只猫永久性大脑中动脉闭塞（MCAO）之前及之后长达24小时，使用15O稳态和[18F]氟脱氧葡萄糖方法以及高分辨率正电子发射断层扫描（PET）扫描仪，反复测量了脑血流量（CBF）、脑氧代谢率（CMRO2）、氧摄取分数（OEF）、脑血容量（CBV）和脑葡萄糖代谢率（CMRglc）。同样，在同一时期对3只假手术对照猫进行了研究。通过连续组织学切片确定最终梗死体积。在最终葡萄糖代谢抑制区域，其略大于组织学梗死灶，动脉闭塞后平均CBF立即降至对照值的约40%。如果在实验过程中进一步降至<20%。这种进行性缺血在边缘区最为明显。CMRO2下降程度较小（55%），最终达到其对照水平的约25%。在早期阶段，OEF主要在缺血中心增加。随着时间推移，OEF增加区域从缺血中心向MCA区域周边移动。同时，OEF的进行性继发性降低与CBF和CMRO2的进一步降低表明了中心坏死的发展。这些发现强烈提示存在动态半暗带。在5只发生完全性MCA梗死的猫中，24小时后对侧半球CBF降低而OEF增加，提示全脑损伤。这种效应可能是由于组织学上发现的广泛脑水肿，以及在实验条件下假手术对照猫1天后也观察到的非特异性CBF降低和OEF升高所解释。在1只猫中，皮质OEF仅短暂增加。最终CMRO2和CMRglc恢复正常，最终梗死灶较小。本研究表明，急性区域病理生理变化可通过多变量PET在猫中反复评估。在MCA闭塞后数小时内可检测到存活组织，并且随着时间推移可追踪灌注不良区域向坏死或保存组织的转变。目前的结果支持动态半暗带的概念，其中长达24小时组织损伤从缺血中心向周边逐渐扩散。连续高分辨率PET可深入了解区域病理生理动态，从而可能推动合理治疗策略的发展。
