Sequential Studies of Severely Hypometabolic Tissue Volumes After Permanent Middle Cerebral Artery Occlusion

124

Summary:The wider clinical acceptance of thrombolytic therapy for ischemic stroke has focused more attention on experimental models of reversible focal ischemia. Such models enable the study of the effect of ischemia of various durations and of reperfusion on the development of infarc tions. We used high-resolution positron emission tomo graphy (PET) to assess cerebral blood flow (CBF), cere bral metatfolic rate of oxygen (CMR02), oxygen extraction fraction (OEF), and cerebral metabolic rate of glucose (CMRglc) before, during, and up to 24 h after middle cere bral artery occlusion (MCAO) in cats. After determination of resting values, the MCA was occluded by a transorbital device. The MCA was reopened after 30 min in five, after 60 min in 11, and after 120 min in two cats. Whereas all cats survived 30-min MCAO, six died after 60-min and one after 120-min MCAO during 6-20 h of reperfusion. In those cats surviving the first day, infarct size was determined on serial histologic sections. The arterial occlusion immedi ately reduced CBF in the MCA territory to <40% of con trol, while CMROz was less affected, causing an increase in OEF. Whereas in the cats surviving 24 h of reperfusion after 60-and 120-min MCAO, OEF remained elevated throughout the ischemic episode, the initial OEF increase had already disappeared during the later period of ischemia in those cats that died during the reperfusion period. After and CMRglc, large infarcts developed, and intracranial pres sure increased fatally. In those surviving the day after MCAO, increased OEF persisted over the ischemic epi sode, postischemic hyperperfusion was less severe and shorter, and the perfusional and metabolic defects as well as the final infarcts were smaller. These results stress the importance of the severity of ischemia for the further course after reperfusion and help to explain the diverging outcome after thrombolysis, where a relation between the residual flow and the effectiveness of reperfusion was also observed.

Section: Discussion Experimental Modelmentioning

confidence: 94%

Repeat Positron Emission Tomographic Studies in Transient Middle Cerebral Artery Occlusion in Cats: Residual Perfusion and Efficacy of Postischemic Reperfusion

Heiss

Graf

Löttgen

et al. 1997

124

“…Watabe et al (2002) showed that CBF images can be quantitated at much shorter interval than the previous protocol, typically at 90 secs, from sequential PET scanning Altman et al (1991) obtained OEF values of 0.5370.13 from arteriosinus blood sampling. Using steady-state PET, others have measured OEFs ranging from 0.42 to 0.58 in normal tissues of anesthetized monkeys (Altman et al, 1991;Pappata et al, 1993;Touzani et al, 1995;Young et al, 1996;Schumann et al, 1996;Frykholm et al, 2000). Moreover, the values of gCBF in the present PET study were 3079 mL 100/g min from three-step ARG, 3079 mL 100/g min from Previously reported values varied from 27 to 37 mL 100/g min for CBF and 2.4 to 3.4 mL 100/g min for CMRO 2 (Altman et al, 1991;Pappata et al, 1993;Touzani et al, 1995;Young et al, 1996;Schumann et al, 1996;Frykholm et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Using steady-state PET, others have measured OEFs ranging from 0.42 to 0.58 in normal tissues of anesthetized monkeys (Altman et al, 1991;Pappata et al, 1993;Touzani et al, 1995;Young et al, 1996;Schumann et al, 1996;Frykholm et al, 2000). Moreover, the values of gCBF in the present PET study were 3079 mL 100/g min from three-step ARG, 3079 mL 100/g min from Previously reported values varied from 27 to 37 mL 100/g min for CBF and 2.4 to 3.4 mL 100/g min for CMRO 2 (Altman et al, 1991;Pappata et al, 1993;Touzani et al, 1995;Young et al, 1996;Schumann et al, 1996;Frykholm et al, 2000). Variations are because of the differences in monkey species, physiologic conditions, anesthetic agent used, PET scanner, and methodology; the current results clearly show that the DARG method can be used to determine these physiologic parameters with a high degree of accuracy.…”

Section: Discussionmentioning

confidence: 99%

Rapid Quantitative Measurement of CMRO₂ and CBF by Dual Administration of ¹⁵O-Labeled Oxygen and Water During a Single PET Scan—a Validation Study and Error Analysis in Anesthetized Monkeys

Kudomi

Hayashi

Teramoto

et al. 2005

101

Cerebral blood flow (CBF) and rate of oxygen metabolism (CMRO 2 ) may be quantified using positron emission tomography (PET) with 15 O-tracers, but the conventional three-step technique requires a relatively long study period, attributed to the need for separate acquisition for each of 15 O 2 , H 2 15 O, and C 15 O tracers, which makes the multiple measurements at different physiologic conditions difficult. In this study, we present a novel, faster technique that provides a pixel-by-pixel calculation of CBF and CMRO 2 from a single PET acquisition with a sequential administration of 15 O 2 and H 2 15 O. Experiments were performed on six anesthetized monkeys to validate this technique. The global CBF, oxygen extraction fraction (OEF), and CMRO 2 obtained by the present technique at rest were not significantly different from those obtained with three-step method. The global OEF (gOEF) also agreed with that determined by simultaneous arterio-sinus blood sampling (gOEF AÀV ) for a physiologically wide range when changing the arterial PaCO 2 (gOEF ¼ 1.03gOEF AÀV þ 0.01, Po0.001). The regional values, as well as the image quality were identical between the present technique and three-step method for CBF, OEF, and CMRO 2 . In addition, a simulation study showed that error sensitivity of the present technique to delay or dispersion of the input function, and the error in the partition coefficient was equivalent to that observed for three-step method. Error sensitivity to cerebral blood volume (CBV) was also identical to that in the three-step and reasonably small, suggesting that a single CBV assessment is sufficient for repeated measures of CBF/CMRO 2 . These results show that this fast technique has an ability for accurate assessment of CBF/CMRO 2 and also allows multiple assessment at different physiologic conditions.

“…20,21 The CBV correction was performed for rCBF, rCMRO 2 , and regional oxygen extraction fraction measurements.…”

Section: Positron Emission Tomography Analysis In Monkey Brainmentioning

confidence: 99%

PET Imaging of Ischemia-Induced Impairment of Mitochondrial Complex I Function in Monkey Brain

Tsukada

Ohba

Nishiyama

et al. 2014

To assess the capability of 18 F-2-tert-butyl-4-chloro-5-{6-[2-(2-fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ( 18 F-BCPP-EF), a novel positron emission tomography (PET) probe for mitochondrial complex I (MC-I) activity, as a specific marker of ischemia-induced neuronal death without being disturbed by inflammation, translational research was conducted using an animal PET in ischemic brains of Cynomolgus monkeys (Macaca fascicularis). Focal ischemia was induced by the right middle cerebral artery occlusion for 3 hours, then PET scans were conducted at Day-7 with 15 O-gases for regional cerebral blood flow (rCBF) and regional cerebral metabolism of oxygen (rCMRO 2 ), and 18 F-BCPP-EF for MC-I with arterial blood sampling. On Day-8, the additional PET scans conducted with 11 C-flumazenil ( 11 C-FMZ) for central-type benzodiazepine receptors, 11 C-PBR28 for translocator protein, and 18 F-fluoro-2-deoxy-D-glucose ( 18 F-FDG) for regional cerebral metabolic rate of glucose (rCMRglc). The total distribution volume (V T ) values of 18 F-BCPP-EF showed the significant reduction in MC-I activity in the damaged area at Day-7. When correlated with rCBF and rCMRO 2 , the V T values of 18 F-BCPP-EF provided better correlation with rCMRO 2 than with rCBF. In the inflammatory regions (region of interest, ROI PBR ) of the ischemic hemisphere detected with 11 C-PBR28, higher 18 F-FDG uptake and lower V T of 18 F-BCPP-EF, 11 C-FMZ, and rCMRO 2 than those in normal contralateral hemisphere were observed. These results strongly suggested that 18 F-BCPP-EF could discriminate the neuronal damaged areas with neuroinflammation, where 18 F-FDG could not owing to its high uptake into the activated microglia.