Cerebral Blood Flow Studies Using N-Isopropyl 1-123p-Iodoamphetamine

HIDENORI KOBAYASHI, M.D. , MINORU HAYASHI, M.D. , HIROKAZU KAWANO, M.D. ,

YUJI HANDA, M.D. , JUNICHI NOZAKI, M.D. , SHINJIRO YAMAMOTO, M.D. ,*

AND HIROSHI MATSUDA, M.D. t

293

SUMMARY Twenty patients with stroke were studied for cerebral blood perfusion abnormalities usingN-isopropyl 1-123 p-iodoamphetamine (IMP) and rotating dual gamma camera emission computed tomog-raphy (ECT). After a single scan, multiple transverse, coronal and sagittal section images were reconstruct-ed with a minicomputer. In eighteen patients, we determined the values of regional cerebral blood flow(rCBF) in the region of interest using an image. Transmission computed tomography (CT) studies were alsoperformed on the same day. ECT showed cerebral perfusion abnormalities in all cases, while CT showedabnormalities in only 10 cases. This technique seems to be useful for evaluating the rCBF in the deep brain.

Stroke Vol 16, No 2, 1985

N-ISOPROPYL 1-123 P - I O D O A M P H E T A M I N E

(IMP) has been reported to be useful for imaging rela-tive brain perfusion because in rat brain first pass ex-traction efficiency was high and physical properties of1-123 (T'/2 = 13 hr., 159KeV photon) were favorablefor scanning.1 2 Kuhl et al3-4 reported that IMP is ahighly lipidsoluble radiopharmaceutical and its lipo-solubility and pH gradient between blood (pH 7.4) andthe interior of the brain cells (pH 7.0) enables it tocross the blood brain barrier and to concentrate in braincells and that the value of whole-brain CBF of humancontrols was 47.2 ± 5.4 ml/100 g/min by the arterialinput sampling method using IMP and single-photonemission computed tomography (ECT). We deter-mined the value of regional cerebral blood flow (rCBF)in stroke patients with IMP and rotating dual gammacamera emission computed tomography. In this paperwe describe the advantages of this method.

Clinical materials and methodsTwenty patients were studied between December

1983 and March 1984 at the University Hospital ofKanazawa. There were 9 women and 11 men, whoranged in age from 12 to 76 years of age with a meanage of 51 years. All were stroke patients diagnosed byangiography; 10 with a cerebral aneurysm with vaso-spasm, 2 with an occlusion of the internal carotid ar-tery (IC), one with an IC stenosis, 3 with ah occlusionof the middle cerebral artery, one with Moyamoyadisease, one with RIND, one with a cerebellar AVMand one with a pontine hemorrhage (table 1). Fourpatients had extracranial-intracranial (EC-IC) bypassoperations. In three of them, CBF studies were donebefore and after bypass surgery. CBF was measured byIMP and rotating dual gamma camera emission com-puted tomography (ECT) equipped with medium ener-gy collimator. An arterial line was placed in the leftradial artery in 18 patients and connected to a Harvard

From the Department of Neurosurgery, Fukui Medical School, Ma-tsuoka, Fukui 910-11, Japan; and the Departments of Neurosurgery,*and Nuclear Medicine,t University of Kanazawa, 13-1 Takaramachi,Kanazawa 920, Japan.

Address correspondence to: Dr. Hidenori Kobayashi, Department ofNeurosurgery, Fukui Medical School, Matsuoka, Fukui 910-11, Japan.

Received July 26, 1984; revision #1 accepted September 10, 1984.

pump. IMP (1.5-3 mCi) was injected into an arm vein.At the same time an arterial blood sample was with-drawn at a constant speed of 1.2 ml/min for 5 minutes.The IMP input curve was recorded. Figure 1 shows thetime course of brain and lung activity after intravenousinjection of IMP. The lung activity decreases rapidlyand the activity curve of the brain reaches a plateauafter about 30 minutes. Scanning was started 35 min-utes after IMP injection.

The equation for determining rCBF is as follows: F= 100 RCb/(NA) where F is rCBF in ml/100 g/min, Ris the constant withdrawal rate of arterial blood in ml/min, Cb is the brain activity concentration in /u.Ci/g, Ais the total activity (5 min) in the withdrawn arterialwhole blood in /aCi and N is the fraction part of arterialwhole blood activity representing unmetabolized IMP.We also used 0.75 as the value of N as determined innormal humans by Kuhl et al.4 Cb and A were deter-mined by ECT and counting in a well counter, respec-tively. The full width at half maximum (FWHM) spa-tial resolution was 2.0 cm within the image plane.After a single scan, multiple transverse, coronal andsagittal slices were reconstructed with a Scintipac2400S (Shimazu Co., Ltd., Kyoto, Japan). The valuesof rCBF were calculated in the regions of interest(ROI: 5 x 5 pixels) of each image. All patients hadtransmission computed tomography (CT) with a EMI-CT 1010 or GE-CT 8800 scanner on the same day. Therelationship between the abnormalities of cerebralblood perfusion on ECT, low density areas on CTscans and neurological findings is reported in thispaper.

ResultsTwenty-three studies were performed in twenty pa-

tients. Twenty-one studies in eighteen patients wereperformed to quantify rCBF by analyzing the ROI ac-tivity concentration. In all the patients with stroke,ECT studies showed abnormal results with focal areasof decreased flow in 18 patients and with diffuse lowperfusions in 2 patients, respectively. CT demonstrat-ed low density areas in 8 patients on the day of ECTstudy. In three patients, low density areas developedone or two days later. In the remaining nine cases,there was no low density area on the CT scan (table 1).

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294 STROKE VOL 16, No 2, MARCH-APRIL 1985

TABLE 1 Clinical, Emission Computed Tomography (ECT) and X-ray Computed Tomography (CT) Features of 20Patients

Case

1

2

.14

S

67

I

9

mii

i i

13

14

15

16

17

18l i

20 ^

Age/Sex

46

40

49

40

53

57

58

50

76

68

41

61

76

12

56

63

47

54

17

50

F

M

F

M

F

M

F

M

M

F

M

F

F

M

M

F

M

M

F

M

Diagnosis

Aneurysm (Ant Com)

Aneurysm (Ant Com + MCA)

Aneurysm (1-Ophthalmic)

r-MCA Occlusion

RIND

1-IC Stenosis

Aneurysm (r-Ophthalmic)

1-IC Occlusion

1-MCA Occlusion

1-MCA Occlusion

Aneurysm (Ant Com)

Aneurysm (1-Ophthalmic)

Aneurysm (r-Ophthalmic)

Moyamoya disease

r-IC Occlusion

Aneurysm (Ant Com)

Aneurysm (Ant Com)

Aneurysm (PICA)

Cerebellar AVM

Pontine Hemorrhage

ECT lowperfusion

focal

focal

focal

focal

focal

focal

focal

focal

diffuse

focal

focal

focal

focal

focal

focal

focal

focal

diffuse

focal

focal

CT lowdensity

( + )

( - )

( + )

( + )

( - )

( + )

( - ) — ( + )

( - )

+

( - ) — ( + )

( - )

( - )

( + )

( - ) — ( + )

( - )

( - )

( - )

( - )

( - )+

Neurologicalfindings

disorientation

normal

disdrieri'tation

1-hemiplegia

normal

r-hemiparesis

stupor, 1-hemiparesis

aphasia, r-hemiparesis

stupor, 1-hemiplegia

stupor, r-hemiparesis

normal

normal

disorientation

1-hemiparesis

normal

1-hemiparesis

disorientation

coma

ataxia

stupor, quadriplegia

Ant Com = anterior communicating artery; MCA = middle cerebral artery; IC = internal carotid artery; PICA =posterior inferior cerebellar artery.

The abnormality demonstrated by ECT was more ex-tensive thai) that demonstrated by CT scan. The CBFstudy by ECT was compatible with neurological defi-cits. The coronal slices in ECT were valuable in deter-mining the vessels responsible for the ischemia, andthe sagittal slices were also valuable in examining themotor and sensory cortex. The following three casesillustrate the capabilities of this method.

3275

e

I

30 Kin

FIGURE 1. Time course of brain and lung activity after intra-venous injection of IMP. The lung activity decreases rapidlyand the activity curve of the brain reaches a plateau after about30 minutes.

Case 5The patient had hypesthesia on the left side and left

homoriymous hemianopsia for seven days and 2mbnths before ECT study. She recovered from herillness completely. There was no abnormality on theCT scan or angiography. Figure 2 shows the transverseslice 5 cm above the OM-line and the CBF values are

FIGURE 2. rCBF values of the patient. ROI 4: 37, 5: 36, 6:39, 7: 38, 8: 38, 9: 31, 10: 43, 11: 40 mlllOO glmin.

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CEREBROVASCULAR BLOOD FLOW STUDIES WITH \MP/Kobayashi et al

FIGURE 3. CT scan shows no low density area. On the eighthday after the stroke.

37 miyiOO g/min in ROI4 of the left frontal lobe, 36 inROI 5 of the right frontal lobe, 39 in ROI 6 of the lefttemporal lobe, 38 in ROI 7 of the right temporal lobe,38 in ROI 8 of the left occipital lobe, 31 in ROI 9 of theright occipital lobe, 43 in ROI 10 of the left basalganglia and 40 in ROI 11 of the right basal ganglia.The CBF value in the right occipital lobe is decreasedby 18% compared to the contralateral ROI. The de-crease in CBF is compatible with the history of visualfield defect.

Case 8This is a patient with an angiographically verified

occlusion of the left IC. Figure 3 shows no low densityarea on the CT scan on the eighth day after the stroke.He had a EC-IC bypass operation a week later. Figure4 demonstrates the slice 7 cm above the OM-line, pre-(left) and post-operation (right). The CBF values inthis slice are 31 ml/100 g/min in the right frontal lobe,23 in the left frontal, 28 in the right parietal and 23 inthe left parietal lobe before the operation, and 40 in theright frontal, 30 in the left frontal, 46 in the rightparietal and 29 in the left parietal lobe after the oper-ation, respectively. The bypass operation resulted in asignificant increase in the CBF of the left hemisphere

_ - . - > • •—

FIGURE 5. This image demonstrates low perfusion in the rightfrontal lobe.

as well as the right hemisphere. He recovered from theright hemiparesis and aphasia after this surgery.

Case 14

This patient is a young boy who had the suddenonset of a left hemiparesis. There was no abnormalityin the CT scan on that day. It showed a low densityarea in the right frontal lobe next day. He was diag-nosed as having "Moyamoya" disease by angiog-raphy. An ECT study was performed on the day of thestroke. Figure 5 shows low perfusion in the right fron-tal lobe. The CBF values in the frontal lobes were 32ml/100 g/min on the left side and 21 (66%) on the rightside, respectively. He recovered from the hemiparesisduring conservative therapy.

DiscussionThis study attempts to demonstrate that three dimen-

sional maps and values for CBF can be accuratelyobtained by means of available technology and IMP.CT provides accurate imaging of cerebral anatomy,but there are no abnormalities on a CT scan unless

FIGURE 4. The slice 7 cm above the OM-line Pre-(left) and post-operation (right). The bypass operation increased CBFsignificantly.

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296 STROKE VOL 16, No 2, MARCH-APRIL 1985

tCBF values are reduced below 34% to 26%.5 Thebrain may appear normal by CT for several days afteran acute interruption of CBF.6 The recent developmentof positron-emission computed tomography (PET)provides us with three dimensional images of cerebralmetabolism as well as CBF. But the enormous cost ofpositron camera, cyclotron and radiopharmacy greatlyrestricts the application of this technique. On the otherhand, the ECT technique is more practical because ofits low cost. Several single-photon emitting radio-pharmaceuticals have been developed to measureCBF.7"10 The rotating gamma camera system has lessresolution and sensitivity than the multidetector sys-tem," u but the images of IMP appear to have gooddiagnostic quality.13

When injected intravenously, all IMP is extractedby the lungs on the first pass, it is then rapidly releasedinto the blood according to a multiexponential func-tion.4 " In humans, IMP appears to reach equilibriumin the brain approximately 15 minutes after the injec-tion and the distribution remains relatively stable for atleast two hours.4-l2 In our cases, time activity curvesreached plateaus about 30 minutes after IMP injection.

Winchell et al2 suggested that IMP was bound in thebrain to high-capacity, relatively non specific receptorsites for amines and that delayed distribution in thebrain was related to the distribution of amine bindingsites. Kuhl et al4 showed good correlation betweenIMP deposition and local CBF as measured by micro-sphere extraction in dogs. We obtained good CBF val-ues in ischemic lesions as well as intact region. But it isnot known how trapping and release mechanisms forIMP in ischemic lesion are affected by the changes inlocal metabolism, pH, permeability or receptor sites.The further research is being studied on this point.

In the case of regional or global ischemia due tospasm after a subarachnoid hemorrhage, early angiog-raphy and surgery are thought to be contraindicated.13

The rapid localization of IMP after intravenous injec-tion provides a major advantage in the study of dis-eases such as stroke and epilepsy. This means that thedistribution of CBF under certain precisely monitoredconditions can be recorded for late analysis. ECT stud-ies have also been reported to localize epileptic seizurefoci more specifically than an EEC'7

That the flow abnormality demonstrated by ECTwas usually more extensive than that seen by CT sug-gests that the functional abnormality is more extensivethan the area of actual cell death.17 ECT is a promisingmethod of identifying zones with lesser degrees ofischemia and evaluating operative results such as ei-ther EC-IC bypass or endarterectomy.

AcknowledgmentsWe would like to thank Miss H. Murata for typing the manuscript.

We also express appreciation to Medi-Physics Inc., Japan which sup-plied the IMP.

References1. Winchell HS, Baldwin RM, LinTH: Development of 1-123 labeled

amines for brain studies: localization of 1-123 iodophenyl-alkylamines in rat brain. J Nucl Med 21: 940-946, 1980

2. Winchell HS, Horst WD, Braun L et al: N-isopropyl('23I)p-io-doamphetamine: Single-pass brain uptake and washout; binding tobrain synaptosomes; and localization in dog and monkey brain. JNucl Med 21: 947-952, 1980

3. Kuhl DE, Wu JL, Lin TH, Selin C, Phelps M: Mapping localcerebral blood flow by means of emission computed tomography ofN-isopropyl-p l23I-iodoamphetamine (IMP). J Cereb blood flowMetab 1 (suppl 1): s25-s26, 1981

4. Kuhl DE, Barrio JR, Huang S-C et al: Quantifying local cerebralblood flow by N-isopropyl-p-('23I) iodoamphetamine (IMP) to-mography. J Nucl Med 23: 196-203, 1982

5. Yamamoto YL, Little J, Meyer E, Thompson C, Ethier R, FeindelW: Evaluation of 77Kr positron emission tomographic studies instroke. J Comput Assist Tomogr 2: 663-664, 1978

6. Campbell JK, Houser OW, Stevens JC et al: Computed tomog-raphy and radionuclide imaging in the evaluation of ischemicstroke. Radiology 126: 695-702, 1978

7. Maeda T, Matsuda H, Hisada K et al: Three-dimensional regionalcerebral blood perfusion images with single-photon emission com-puted tomography. Radiology 140: 817-822, 1981

8. Bonte RJ, Stokely EM: Single-photon tomographic study of re-gional cerebral blood flow after stroke: concise communication. JNucl Med 22: 1049-1053, 1981

9. Vorstrup S, Hemmingsen R, Henriksen L, Lindewald H, EngellHC, Lassen NA: Regional cerebral blood flow in patients withtransient ischemic attacks studied by Xenon-133 inhalation andemission tomography. Stroke 14: 903-910, 1983

10. Kung HF, Tramposch KM, Blau M: A new brain perfusion imag-ing agent: (1-123) HIPDM: N,N,N'-Trimethyl-N'-(2-Hydroxy-3-Methyl-5-Iodobenzyl)-l,3-Propanediamine. J Nucl Med 24: 66-72, 1983

11. Hill TC, Magistretti PL, Holman BL et al: Assessment of regionalcerebral blood flow (rCBF) in stroke using SPECT and N-isopro-pyl-(I-123)-p-iodoamphetamine (IMP). Stroke IS: 40-45, 1984

12. Lassen NA, Henriksen L, Holm S et al: Cerebral blood-flow to-mogaphy: Xenon-133 compared with isopropyl-amphetamine-Io-dine-123: Concise communication. J Nucl Med 24: 17-21, 1983

13. Fazio F, Geradin P, Gilardi MC: Single photon emission computedtomography (SPECT) evaluation of the brain imaging agent, (I-123) HIPDM in man with rotating gamma camera. J Nucl Med 24:5, 1983

14. Hill TC, Holman BL, Lovett R et al: Initial experience with SPECT(single-photon computed tomography) of the brain using N-isopro-pyl 1-123 p-iodoamphetamine: concise communication. J NuclMed 23: 191-195, 1982

15. Holman BL, Hill TC, Magistretti PL: Emission computed tomog-raphy of the brain with radiolabeled amines. Invest Rad 17: 206-215, 1982

16. Flamm ES: Parasurgical treatment of aneurysms. Clin Neurosurg24: 240-247, 1977

17. Uren RF, Magistretti PL, Royal HD et al: Single-photon emissiontomography: A method of measuring cerebral blood flow in threedimensions (preliminary results of studies in patients with epilepsyand stroke). Med J Aust 1: 411-413, 1983

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H Kobayashi, M Hayashi, H Kawano, Y Handa, J Nozaki, S Yamamoto and H MatsudaCerebral blood flow studies using N-isopropyl I-123 p-iodoamphetamine.

Print ISSN: 0039-2499. Online ISSN: 1524-4628 Copyright © 1985 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Stroke doi: 10.1161/01.STR.16.2.293

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