Potential of Early [18F]-2-Fluoro-2-Deoxy-D-Glucose PositronEmission Tomography for Identifying Hypoperfusion andPredicting Fate of Tissue in a Rat Embolic Stroke Model

Maureen Walberer, DVM*; Heiko Backes, PhD*; Maria A. Rueger, MD; Bernd Neumaier, PhD;Heike Endepols, PhD; Mathias Hoehn, PhD; Gereon R. Fink, MD;

Michael Schroeter, MD; Rudolf Graf, PhD

Background and Purpose—Experimental stroke models are essential to study in vivo pathophysiological processes offocal cerebral ischemia. In this study, an embolic stroke model in rats was applied (1) to characterize early developmentof regional cerebral blood flow and metabolism with positron emission tomography (PET) using [15O]H2O and[18F]-2-fluoro-2-deoxy-D-glucose (FDG); and (2) to identify potential parameters for predicting tissue fate.

Methods—Remote occlusion of the middle cerebral artery was induced in 10 Wistar rats by injection of 4 TiO2

macrospheres. Sequential [15O]H2O-PET (baseline, 5, 30, 60 minutes after middle cerebral artery occlusion) andFDG-PET measurements (75 minutes after middle cerebral artery occlusion) were performed. [15O]H2O-PET data andFDG kinetic parameters were compared with MRIs and histology at 24 hours.

Results—Regional cerebral blood flow decreased substantially within 30 minutes after middle cerebral artery occlusion(41% to 58% of baseline regional cerebral blood flow; P�0.001) with no relevant changes between 30 and 60 minutes.At 60 minutes, regional cerebral blood flow correlated well with the unidirectional transport parameter K1 of FDG inall animals (r�0.86�0.09; P�0.001). Tissue fate could be accurately predicted taking into account K1 and net influxrate constant Ki of FDG. The infarct volume predicted by FDG-PET (375.8�102.3 mm3) correlated significantly withthe infarct size determined by MRI after 24 hours (360.8�93.7 mm3; r�0.85).

Conclusions—Hypoperfused tissue can be identified by decreased K1 of FDG. Acute ischemic tissue can be wellcharacterized using K1 and Ki allowing for discrimination between infarct core and early viable tissue. BecauseFDG-PET is widely spread, our findings can be easily translated into clinical application for early diagnoses ofischemia. (Stroke. 2012;43:193-198.)

Key Words: FDG-PET � macrosphere model � penumbra � PET � prediction � rCBF � stroke

A principle purpose of early imaging after stroke is topredict the fate of tissue and thus identify tissue com-

partments potentially accessible to therapeutic intervention.Imaging of experimental stroke models in the acute phase isessential to study pathophysiological processes related tocerebral ischemia in vivo and forms a basis for the develop-ment of novel therapies.

Positron emission tomography (PET) allows visualizingmolecular and biochemical processes in the living brain.1 Thestandard tracer for measuring regional cerebral blood flow(rCBF) by PET is radiolabeled H2O ([15O]H2O). However,[15O]H2O-PET has some disadvantages, like a short half-life(approximately 2 minutes) of [15O]H2O and a low signal-to-noise ratio.1 Cerebral glucose metabolism can be measured by

PET using [18F]-2-fluoro-2-deoxy-D-glucose (FDG),2–4 atracer that is much more readily available than [15O]H2O.Like glucose, FDG is transported into brain tissue by glucosetransporters and is phosphorylated by the enzyme hexokinase,but, in contrast to glucose, FDG is not further metabolized buttrapped in metabolically active cells.3,4 Previous MRI studiesin rats have suggested parameters like the mismatch ofdiffusion-weighted and perfusion-weighted imaging or appar-ent diffusion coefficient as predictors for final tissue outcomeif acquired during the acute phase of stroke.5–10 However, agenerally accepted method for the prediction of tissue fatefrom MRI data is still lacking.11

The purpose of this PET study in a rat embolic strokemodel was (1) to characterize early alterations of rCBF using

Received April 28, 2011; final revision received August 2, 2011; accepted August 22, 2011.From the Department of Neurology (M.W., M.A.R., G.R.F., M.S.), University Hospital, Cologne, Germany; Max Planck Institute for Neurological

Research (M.W., H.B., M.A.R., B.N., H.E., M.H., M.S., R.G.), Cologne, Germany; and the Institute of Neuroscience and Medicine (INM-3; G.R.F.),Cognitive Neurology Section, Research Centre Juelich, Juelich, Germany.

The online-only Data Supplement is available at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.111.624551/-/DC1.*M.W. and H.B. contributed equally to this work.Correspondence to Heiko Backes, PhD, Max Planck Institute for Neurological Research, Gleueler Street 50, 50924 Cologne, Germany. E-mail

backes@nf.mpg.de© 2011 American Heart Association, Inc.

Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.111.624551

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sequential [15O]H2O-PET; (2) to analyze FDG kinetics inacute ischemic tissue as well as (3) to identify potential param-eters for the early prediction of tissue fate that might support thedevelopment of potential therapeutic interventions.

MethodsAnimals and SurgeryAll animal procedures were in accordance with the German Laws forAnimal Protection and were approved by the local animal carecommittee and local governmental authorities. Male Wistar rats(n�13) from Harlan Winkelmann (Borchen, Germany) weighing305 to 330 g were anesthetized with 5% isoflurane and maintainedwith 2.5% isoflurane in 65%/35% nitrous oxide/oxygen. Throughoutthe surgical procedure, body temperature was maintained at 37.0°Cwith a thermostatically controlled heating pad. Before PET imaging,animals were prepared for ischemia induction by macrosphere modelas described elsewhere.12 Briefly, the right common carotid artery,internal carotid artery, and external carotid artery were exposedthrough a midline incision of the neck and the external carotid arteryand the pterygopalatine branch of the internal carotid artery wereligated. A PE-50 catheter was filled with saline and 4 TiO2macrospheres (diameter of 0.315–0.355 mm; BRACE, Alzenau,Germany). This catheter was inserted into the common carotidartery, advanced to the origin of the pterygopalatine artery, and fixedin place. After placing the rats within the micro-PET scanner andrunning baseline measurements, macrospheres were injected througha saline-filled catheter placed in the internal carotid artery to occludemiddle cerebral artery; n�13). After PET imaging, the catheter wasremoved and the animals were allowed to recover.

Positron Emission TomographyPET imaging was performed on a microPET Focus 220 scanner(Concorde Microsystems, Inc, Knoxville, TN; 63 image planes;1.5-mm full width at half maximum) as described elsewhere.13

After a 10-minute transmission scan for attenuation correction,rats received an intravenous bolus injection of [15O]H2O (1.6–2.4mCi/rat) before as well as 5, 30, and 60 minutes after MCAO withoutchanging the position of the animals in the PET scanner. Emissiondata were acquired for 2 minutes. Thereafter, an intravenous bolus ofFDG (1.4–2.0 mCi/rat in 500 �L) was injected into the tail vein at75 minutes after embolization of macrospheres, and emission datawere acquired for 60 minutes. After histogramming in timeframes of6�30 seconds, 3�60 seconds, 3�120 seconds, and 12�240 secondsand Fourier rebinning, data were reconstructed using a2-dimensional filtered back projection. An image derived inputfunction was extracted from the FDG-PET data and parametricimages of the kinetic constants were determined by voxelwiseapplication of a 2-tissue-compartment kinetic model with 4 rateconstants (K1, transport from blood to brain; k2, transport from thebrain to blood; k3, phosphorylation; k4, dephosphorylation).14

K1 is related to rCBF by K1�rCBF�(1�e�PS/rCBF), where PS isthe permeability surface product of FDG.15 In hypoperfused tissue,(rCBF��PS): K1�rCBF.

The metabolic rate constant or net influx rate constant is given byKi�K1�k3/(k2�k3). In the autoradiographic method, the cerebralmetabolic rate of glucose consumption CMRglc is given by: CMR-glc�1/LC Ki Cp, where LC is the lumped constant and Cp the plasmaglucose level.3

Characterization of Tissue With K1 and KiTaking parametric images of K1 and Ki, each image voxel can bedisplayed in a K1–Ki diagram. We hypothesized that tissue conditionwas related to its location in the K1–Ki diagram. Healthy tissue(contralateral hemisphere) could be characterized by the center ofmass (CM) and the SD. Affected tissue was shifted with respect tothe healthy tissue by a shift to lower K1 and higher Ki. Fromcomparison with the infarct measured by T2-weighted MRI 24 hoursafter MCAO, the following line could be defined that separateshealthy from later infarcted tissue in the early K1–Ki diagram: tissue

with Ki�m K1�b (m�(KiCM�0.75 SDKi)/(K1CM�0.75SDK1�0.04), b��0.04 m) had a high risk of being infarcted after 24hours. Furthermore, we could divide the tissue being infarcted after 24hours into 2 groups: (1) early viable tissue with Ki�KiCM�0.75 SDKi;and (2) early infarct core (Ki�KiCM�0.75 SDKi).

Radiochemistry[15O]H2O was synthesized by the reduction of [15O]O2 with H2 gas(catalyzed by Pd black at 140°C). The synthesized [15O]H2O gas,trapped in a 500 �L saline solution, was used for animal experiments.

FDG was produced as described previously.13

Magnetic Resonance ImagingTwenty-four hours after induction of ischemia, 8 rats were reanes-thetized with isoflurane, and T2-weighted MRI on a 4.7-T BioSpecsystem (Bruker BioSpin, Ettlingen, Germany) was performed asdescribed elsewhere.13

HistologyTwenty-four hours after MCAO, 3 animals (2 without MRI investi-gation) were decapitated under deep anesthesia. The brains werestained with hematoxylin and eosin according to the stainingprotocol given by Merck (Merck KGaA, Darmstadt, Germany).

Animals without hematoxylin and eosin staining were not eutha-nized after 24 hours but included into a different study on thelong-term development of stroke.

Image AnalysisFor coregistration of PET, MRI, and histological images, the imageanalysis software VINCI (Max Planck Institute for NeurologicalResearch, Cologne, Germany)16 was used. Additional coregistrationto an anatomic data set of a 3-dimensional rat brain atlas constructedfrom the brain slices presented by Swanson17 was performed.

Infarct Volume QuantificationOn T2-weighted images of MRI, the lesion volume in millimeters cubedwas detected by computer-aided manual tracing of the hyperintenselesions using the image analysis software VINCI.16 The edema-corrected infarct volume was quantified as described elsewhere.18

Volume of Interest GridBased on the 3-dimensional anatomic data set, volumes of interest(VOIs; 2�2�2 mm3) were placed in the ipsilateral and correspond-ing positions of the contralateral hemisphere (Supplemental Figure I;http://stroke.ahajournals.org). rCBF was assessed as percentage in-jected dose of [15O]H2O averaged over 2 minutes acquisition time.For the analysis of the rCBF development over time, rCBF wascalculated as percentage of baseline rCBF in [15O]H2O-PET. Abso-lute values of rCBF evaluated by [15O]H2O-PET at 60 minutes andK1 of FDG-PET were compared.

Statistical AnalysisStatistical analysis was performed with SigmaPlot 11 (Systat Soft-ware Inc). Two-way analyses of variance for repeated measurementswith a post hoc test of Holm-Sidak were used to analyze the rCBFdevelopment in each animal (factors: time [baseline, 5 minutes, 30minutes, 60 minutes] and VOI [infarcted VOIs versus correspondingcontralateral VOIs]). Statistical significance was set at �5% (P�0.05).

ResultsPostmortem, 3 animals showed no occlusion of the middlecerebral artery mainstem after the injection of macrospheresand were excluded from the study.

rCBF Development After MCAOAfter the injection of 4 macrospheres, all animals (n�10)showed a uniform response of rCBF within the first 60

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minutes. The rCBF development in the ipsi- and contralateralhemisphere of 2 representative animals is displayed in Figure1. In all animals, rCBF in the infarct core (later determinedhistologically) significantly decreased within the first 30minutes after MCAO (at 5 minutes to 43%–76% and at 30minutes to 38%–65% of baseline rCBF). This was reflectedby a significant main effect of factor time (F[3,30 –129]�174.68; P�0.001). Post hoc comparison revealed thatwithin the infarcted VOIs, the time points 5, 30, and 60minutes were significantly different from baseline rCBF.After 30 minutes, rCBF remained stable; there was norelevant difference (�3%) in rCBF between 30 and 60minutes (Figure 1). The rCBF of the corresponding VOIs ofthe contralateral hemisphere stayed between 90% and 110%of the baseline level.

Comparison of [15O]H2O-PET and K1of FDG-PETK1 is the rate constant for FDG transport from blood intobrain tissue. In hypoperfused tissue, K1 is related to rCBF.Both, [15O]H2O-PET at 60 minutes and K1 of FDG-PET at75 minutes showed very similar patterns of the ischemictissue (Figure 2A–B). In each animal, rCBF within theischemic hemisphere determined by [15O]H2O-PET at 60minutes correlated well to the K1 of FDG-PET (r�0.86�0.09;P�0.001; exemplary correlation of 1 animal in Figure 2C).In the overall analysis of all VOIs in the ipsi- andcontralateral hemispheres of all animals, the relation of[15O]H2O-PET at 60 minutes and K1 of FDG-PET could befitted by the function K1�a�(H2O-PET)�(1�exp[�b/(a�H2O-PET]) with a�32.69�1.33 mL/cm3/min and

Figure 1. rCBF development over time was assessed by [15O]H2O-PET at 0, 5, 30, and 60 minutes after MCAO and is displayed in 2representative animals (A–B). The infarcted areas are highlighted by turquoise contours. The time course of rCBF on the basis of a VOIanalysis is displayed in 3-dimensional diagrams showing rCBF at each time point as a percentage of baseline for each VOI. The VOIaxes are sorted individually by the ipsilateral rCBF as percentage of baseline in an ascending order (see Supplemental Table I). In thebottom row, T2-weighted MRI (left) and hematoxylin and eosin staining (right) verified the ischemic damage 24 hours after MCAO, andthe position of macrospheres within the circle of Willis is illustrated. rCBF indicates regional cerebral blood flow; PET, positron emissiontomography; MCAO, middle cerebral artery occlusion; VOI, volume of interest; ICA, internal carotid artery; MCA, middle cerebral artery;ACA, anterior cerebral artery.

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b�0.1906�0.0057 mL/cm3/min (P�0.001; Figure 2D)confirming the theoretical relation of rCBF and K1 (see“Materials and Methods”). Note that “b” is the permeabil-ity surface product of FDG.

Characterization of InfarctIn all animals, we determined the infarct volume after 24hours either histologically (n�3; 323.7�145.0 mm3; Figure1A) or by MRI (n�8; 360.8�93.7 mm3; Figure 1B; exem-plary coronal section of 2 animals in Figure 1, bottom). Exvivo, we assessed the position of the TiO2 spheres in thecircle of Willis, which could be found within the internalcarotid artery/middle cerebral artery vessel arborization blockingthe proximal middle cerebral artery (examples of 2 animals inFigure 1, bottom).

Tissue Characterization and Prediction ofInfarct OutcomeAcute ischemic tissue could be characterized using the netFDG influx rate constant Ki and the rate constant for FDGtransport from blood into brain K1. From comparison with theinfarct at 24 hours after MCAO, we found that tissue fatecould be predicted in the following way: if Ki�m K1�b (see“Materials and Methods”) at 60 minutes after MCAO, thisregion will be infarcted 24 hours later (Figure 3A–B).Furthermore, this tissue with malprediction could be dividedinto 2 classes: (1) immediately damaged tissue with Ki�KiCM�0.75 SDKi constituting the early infarct core; and (2) stillviable tissue (Ki �KiCM�0.75 SDKi), which was predomi-nantly but not only localized between healthy tissue and earlyinfarct core. In some individuals, this early viable tissuecovered �70% of the later infarct volume.

The infarct size predicted with the K1–Ki diagram(375.8�102.3 mm3) and the edema-corrected infarct sizedetermined by T2-weighted MRI (360.8�93.7 mm3;P�0.5) correlated well (r�0.85; P�0.05; Figure 3C).

DiscussionIn this study, we performed remote occlusion of the middlecerebral artery in rats within the �PET scanner leading tofocal cerebral ischemia. In our macrosphere model, theintra-arterial injection of 4 TiO2 spheres leads to permanentMCAO and mimics arterioarterial embolism of “hard” ath-erosclerotic plaque material.19 The macrosphere model seemsto be a relevant model for studying the pathophysiology ofstroke, because arterioarterial embolism is 1 of the mostfrequent causes of stroke in humans.20–22 We have recentlycharacterized early cortical rCBF dynamics in this model byreal-time imaging using Laser Speckle Contrast Imaging.23

Moreover, this model easily allows remote vessel occlusionwithin MRI12,24 and, as we show here, PET scanners.

The injection of macrospheres led to an occlusion of themiddle cerebral artery mainstem and resulted in large infarcts.Using [15O]H2O-PET, we observed the development of anischemic core within the first 30 minutes after induction ofischemia with no relevant changes during the next 30 min-utes, which is in accordance with other permanent rat strokemodels such as photothrombotic model,25 distal MCAO,26,27

and intraluminal suture model.28,29

The rCBF measurements within the ipsilateral hemispherequantified by [15O]H2O-PET at 60 minutes, and by K1 ofFDG, correlated well in each animal. Thus, the K1 parameterof FDG is a reliable measure for rCBF in hypoperfused tissue.From fitting of the theoretical function of the relation of K1

Figure 2. rCBF in the ipsilateral hemisphere determined by[15O]H2O-PET at 60 minutes after MCAo (A), K1 of FDG (B), andthe correlation of rCBF and K1 (C) in 1 exemplary animal. K1 ofFDG and rCBF in the ipsi- and contralateral hemispheres of allanimals confirmed theoretical relation of the parameters (D).rCBF indicates regional cerebral blood flow; PET, positron emis-sion tomography; MCAO, middle cerebral artery occlusion; FDG,[18F]-2-fluoro-2-deoxy-D-glucose.

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to rCBF, the average permeability surface product of FDGwas determined as 0.1906�0.0057 mL/cm3/min, which is inline with the values reported in the literature.30

The major finding of the present study is that the 2 kineticparameters K1 and Ki of FDG have a high diagnosticpotential for the analysis of acute ischemic tissue. In hypoper-fused regions, K1 is approximately equal to cerebral bloodflow, that is, tissue with substantial reduction of cerebralblood flow can be identified by a reduction of K1. The FDGnet influx rate Ki, which depends on transport as well asphosphorylation of FDG, is a measure for tissue viability. Thedifferences of FDG and glucose with respect to transport andphosphorylation have the effect that Ki of FDG is elevated inregions with preserved glucose consumption and reducedtransport (cerebral blood flow, K1).14 We observed that partof the tissue infarcted after 24 hours had normal or elevatedKi at 1 hour after MCAO. In these regions, the reduced bloodflow and thereby glucose supply is compensated by anincrease of phosphorylation rate to maintain cellular energyconsumption.

These findings are in accordance with the increase of theoxygen extraction fraction that has been observed in the earlyischemic tissue and defines the ischemic penumbra.31,32 Thedecrease of oxygen supply as a consequence of the reducedcerebral blood flow is compensated by an increase of oxygenextraction fraction to maintain oxygen consumption. In thesame manner, hexokinase activity (and thereby Ki of FDG) isincreased to maintain glucose consumption in regions withlow cerebral blood flow. Thus, we provide a new method forthe identification of the ischemic penumbra purely based onFDG-PET data.33 Although oxygen extraction fraction mea-surements require an onsite cyclotron due to the shorthalf-life of 15O (2 minutes), FDG is commercially availableand the method is applicable more generally (even clinically)than the oxygen extraction fraction method.

Therefore, our method extends the opportunity for thedetection of an ischemic penumbra to the whole PET com-munity. It was so far limited to PET centers with an onsitecyclotron.

To our knowledge, the power of FDG-PET for the diag-nosis of acute ischemia has not been reported. The results wepresent here can only be obtained using kinetic modeling ofthe PET data. In particular the explicit determination of K1 isrequired. Kinetic modeling was not performed in any of thepublished FDG studies in acute ischemia.34–36

In conclusion, in the macrosphere model for embolicstroke, functionally relevant alterations in rCBF occur be-tween 5 and 30 minutes after induction of ischemia. Kineti-cally modeled FDG-PET is a reliable method for measuringrCBF in acute stroke and allows the identification of primar-ily affected but still viable tissue that is accessible totherapeutic interventions. The relation to diffusion/perfusionweighted MRI in ischemic tissue remains to be investigated.

DisclosuresNone.

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Figure 3. A, K1–Ki diagram of 1 animal. Image voxels identifiedas infarcted in the T2-weighted MRI 24 hours after MCAO (red)were separated from healthy tissue image voxels (ipsilateral inblack, contralateral in blue) by a straight line. Later infarcted tis-sue could be divided into 2 classes: acute viable tissue andinfarct core. B, Image voxels classified as acute viable tissueand infarct core in the K1–Ki diagram marked on K1 and Kiparametric images of FDG in comparison to T2-weighted MRI24 hours after MCAO. C, The infarct volume predicted by K1and Ki of FDG-PET (375.8�102.3 mm3) correlated with theedema-corrected infarct size determined on T2-weighted MRI(360.8�93.7 mm3; r�0.85; P�0.5). MCAO indicates middlecerebral artery occlusion; FDG, [18F]-2-fluoro-2-deoxy-D-glucose; PET, positron emission tomography.

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Hoehn, Gereon R. Fink, Michael Schroeter and Rudolf GrafMaureen Walberer, Heiko Backes, Maria A. Rueger, Bernd Neumaier, Heike Endepols, MathiasIdentifying Hypoperfusion and Predicting Fate of Tissue in a Rat Embolic Stroke Model

F]-2-Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography for18Potential of Early [

Print ISSN: 0039-2499. Online ISSN: 1524-4628 Copyright © 2011 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Stroke doi: 10.1161/STROKEAHA.111.624551

2012;43:193-198; originally published online October 27, 2011;Stroke. 

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SUPPLEMENTAL MATERIAL

A

B

C

S1: Volume of interest (VOI) analysis: The position of VOIs (2x2x2 mm³) is displayed on paramedial (A), intermediate (B) and lateral (C) sagittal brain sections of one hemisphere.

VOI rCBFi(%) rCBFc(%) VOI rCBFi(%) rCBFc(%) 50 13.36 105.03 50 33.03 103.01

Animal A A

51 14.42 95.10 32 34.08 101.40

34 14.69 98.23 15 34.36 100.08

63 16.42 99.65 14 35.19 102.28

33 17.49 105.05 33 36.88 103.07

16 20.84 98.09 49 37.13 98.68

62 21.49 99.74 16 39.44 101.67

15 22.86 104.04 62 39.59 99.92

32 23.66 105.35 48 40.66 104.37

60 24.34 102.51 11 45.24 100.71

46 24.53 100.42 31 46.98 104.19

49 25.41 112.87 26 49.44 104.22

28 25.49 101.10 34 50.21 100.27

52 25.98 97.77 10 51.63 100.52

35 26.35 97.97 27 53.54 101.01

17 26.47 98.46 12 54.45 94.06

45 28.46 100.45 59 54.58 101.84

14 28.61 109.69 9 54.62 99.00

27 32.14 100.64 45 55.20 102.44

59 33.94 102.29 63 55.51 101.89

29 35.85 95.56 60 57.49 100.9247 36.15 102.59 17 57.60 95.5161 36.67 103.21 28 57.74 99.74

48 37.02 99.04 44 58.09 105.73

26 40.71 95.11 8 59.26 99.79

31 41.39 106.18 25 59.92 105.32

44 41.45 101.56 51 60.80 98.90

11 41.71 96.55 58 63.11 103.47

12 44.85 89.40 46 66.15 105.12

10 44.99 100.64 1 70.82 95.29

13 51.08 97.61 29 71.12 100.39

30 51.94 98.64 13 72.22 97.11

22 52.88 87.85 43 73.25 103.34

39 54.77 95.78 35 73.80 100.05

9 54.80 100.40 2 73.96 92.5621 56.00 85.83 4 75.59 96.83

58 56.11 102.68 61 77.11 97.05

40 60.00 93.88 5 77.46 97.39

25 60.67 101.81 19 78.60 101.96

56 62.95 100.85 52 78.64 102.67

20 64.10 92.03 3 78.64 99.06

55 64.57 100.28 20 79.79 104.7243 65.59 115.28 21 80.19 104.4638 65.91 100.17 30 81.25 100.64

5 68.71 93.30 47 81.40 98.25

23 69.41 99.14 22 81.45 95.84

8 69.68 99.42 39 83.04 98.72

4 70.61 92.31 55 83.43 100.47

3 71.18 94.47 6 83.70 93.2619 72.41 96.23 18 84.44 98.81

57 72.91 100.85 37 87.19 100.69

41 73.60 102.81 38 87.59 101.71

6 73.74 95.41 56 87.61 99.56

2 78.10 93.19 54 89.74 102.56

54 78.16 101.62 40 90.19 101.4837 79.54 100.16 36 90.49 99.40

1 82.95 91.07 7 91.27 94.27

18 84.12 98.62 53 92.63 99.85

7 85.53 95.96 23 94.10 98.09

24 87.75 102.00 42 98.38 96.16

36 88.38 106.90 24 99.51 96.72

53 88.63 103.8 57 102.05 99.32

42 94.59 107.89 41 102.60 97.31

nimal B

S2: The individual order of VOIs with the associated rCBF at 60 minutes is displayed as percentage of baseline and presented for the ipsilateral (rCBFi (%)) and contralateral (rCBFc (%)) hemisphere of two representative animals (figure 1). Ipsi- and contralateral VOIs were individually sorted by the rCBFi at 60min, shown as percentage of baseline in ascending order.

Abstract 39

ラット塞栓性脳卒中モデルにおいて [18F]-2-フルオロ-2-デオキシ-D-グルコース陽電子断層撮影法が低灌流を同定し組織の運命を予測する可能性

Potential of Early [18F]-2-Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography for Identifying Hypoperfusion and Predicting Fate of Tissue in a Rat Embolic Stroke Model

Maureen Walberer, DVM1,2; Heiko Backes, PhD2; Maria A. Rueger, MD1,2; Bernd Neumaier, PhD2; Heike Endepols, PhD2; Mathias Hoehn, PhD2; Gereon R. Fink, MD1,3; Michael Schroeter, MD1,2; Rudolf Graf, PhD2

1 Department of Neurology, University Hospital, Cologne, Germany; 2 Max Planck Institute for Neurological Research, Cologne, Germany; and 3 Institute of Neuroscience and Medicine (INM-3), Cognitive Neurology Section, Research Centre Juelich, Juelich, Germany.

Abstract

背景および目的：局所脳虚血のin vivo での病態生理学的過程を研究するには実験的脳卒中モデルが不可欠である。本研究では，ラットの塞栓性脳卒中モデルを用いて，（1）[15O]H2O および [18F]-2- フルオロ -2- デオキシ -D- グルコース（FDG）を用いた陽電子断層撮影（PET）で初期の局所脳血流および代謝の特徴を明らかにし，（2）組織の運命を予測するための潜在的パラメータを同定した。方法：4 つの TiO2 macrosphere の注入により，10 匹のWistar ラットに中大脳動脈の遠位閉塞を誘発した。連続的な [15O]H2O-PET（ベースライン，中大脳動脈閉塞の 5 分，30 分，60 分後）および FDG-PET の測定（中大脳動脈閉塞の 75 分後）を行った。[15O]H2O-PET データおよび FDG動態パラメータを 24 時間時点の MRI および組織像と比較した。結果：局所脳血流量は中大脳動脈閉塞から 30 分以内に大幅に低下し（ベースライン局所脳血流量の 41 ～ 58％，

p ＜ 0.001），30 ～ 60 分の間には有意な変化は認められなかった。60 分の時点では，局所脳血流量は全動物において FDG の一方向性輸送パラメータK1 とよく相関していた（r ＝ 0.86 ± 0.09；p ＜ 0.001）。FDG のK1 および正味流入速度定数Ki を考慮に入れることにより組織の運命を正確に予測できた。FDG-PET により予測された梗塞容積

（375.8 ± 102.3 mm3）は，24 時間後の MRI により測定された梗塞サイズ（360.8 ± 93.7 mm3；r ＝ 0.85）と統計学的に有意に相関していた。結論：FDG のK1 低下により，低灌流組織を同定できる。K1 およびKi を用いて急性虚血組織の特徴を十分に明らかにすることができ，梗塞のコアと初期生存組織を識別することができる。FDG-PET は広く普及していることから，本研究の所見を虚血の早期診断のため臨床に応用するのは容易である。

Stroke 2012; 43: 193-198

図 2

代表的な動物において MCAO から 60 分後の[15O]H2O-PET（A），FDGのK1（B），および rCBF とK1 の相関（C）により明確にされた同側半球の rCBF。全動物の同側および対側半球における FDG のK1 および rCBF により，これらのパラメータの理論上の関連が確認された（D）。rCBF：局所脳血流量，PET：陽電子断層撮影法，MCAO：中大脳動脈閉塞，FDG：[18F]-2-フルオロ-2-デオキシ-D-グルコース。

A 0.009

0.006

0.003

0.000

（注入量の割合/cm3 ）

（mL/cm

3 /min）

[18 F]FDGのK1（mL/cm

3 /min）

[15O]H2O（注入量の割合/cm3）

0.13

0.06

0.00

0.25

0.20

0.15

0.10

0.05

0.00

B

[15O]H2O-PET

of [18F]FDG-PETK1

C

D

0.000 0.002 0.004 0.006

r=0.96

0.008 0.010

[18 F]FDGのK1（mL/cm

3 /min）

[15O]H2O（注入量の割合/cm3）

0.25

0.20

0.15

0.10

0.05

0.000.000 0.002 0.004 0.006 0.008 0.010

同側対側

f(x)=a*x*(1-exp(-b/(a*x)))a=32.6885 ±1.333b=0.190633 ±0.005701

A 0.009

0.006

0.003

0.000

（注入量の割合/cm3 ）

（mL/cm

3 /min）

[18 F]FDGのK1（mL/cm

3 /min）

[15O]H2O（注入量の割合/cm3）

0.13

0.06

0.00

0.25

0.20

0.15

0.10

0.05

0.00

B

[15O]H2O-PET

of [18F]FDG-PETK1

C

D

0.000 0.002 0.004 0.006

r=0.96

0.008 0.010

[18 F]FDGのK1（mL/cm

3 /min）

[15O]H2O（注入量の割合/cm3）

0.25

0.20

0.15

0.10

0.05

0.000.000 0.002 0.004 0.006 0.008 0.010

同側対側

f(x)=a*x*(1-exp(-b/(a*x)))a=32.6885 ±1.333b=0.190633 ±0.005701

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