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In Vivo Quantitation of Regional Cerebral Blood Flow in Glioma and Cerebral Infarction: Validation of the Hipdm­ SPECT Method

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In Vivo Quantitation of Regional Cerebral Blood Flow in Glioma and Cerebral Infarction: Validation of the Hipdm­ SPECT Method 572 In vivo Quantitation of Regional Cerebral Blood Flow in Glioma and Cerebral Infarction: Validation of the HIPDm­ SPECT Method Burton Drayer ," 2 Ronald Jaszczak,' Allan Friedman,3 Robert Albright,'·2 Hank Kung,4 Kim Greer,' Michael Lischko,' Neil Petry,' and Edward Coleman' todine-123 labeled hydroxyiodopropyldiamine (HIPDm) is a a visual or quantitati ve analysis of brain distribution is sufficient for diffusible indicator with an 85% -90% extraction fraction and defining an abnormality when a focal pathologic process is present, stable retention in the brain for more than 2 hr. Equilibrium­ an absolute valu e for rCBF is necessary if studies are to be com­ phase imaging and quantitation using single-photon emission pared in different stages of disease or an analysis is to be made of computed tomographic (SPECT) scanning defined a distribution diffuse, bilaterall y symmetric pathologic processes (e.g., Alzheimer of HIPDm in proportion to regional cerebral blood flow (rCBF). disease, metaboli c encephalopathy). Studies in calves affirmed a close correspondence (r = 0.97) in calculated rCBF between HIPDm and microspheres using the tissue deposition-arterial input function microsphere methodol­ Materials and Methods ogy. Using this same mathematical analysis in vivo, reproducible Isotope Detection rCBF data within the expected range of normal were obtained on repeated studies in the same nonhuman primate. With a The Duke-Siemens SPECT system [14, 15] con sists of two op­ diffuse encephalopathy secondary to subarachnoid blood, a posing large-field-of-view (LFOV) gamma scintillation cameras bilaterally symmetric decrease in rCBF was present. A prominent mounted on a rotatabl e gantry with each head rotating through focal decrease in HIPDm accumulation and calculated rCBF was 360 0 in 2- 26 min . Our studies use low-energy, all-purpose parall el noted with cerebral infarction in the distribution of a ligated (LEAP) or medium-energy collimators. Thirty-two contiguous middle cerebral artery. Patient studies with glioma revealed transaxial secti ons, each 6.4 mm thick, were reconstruc ted from diminished HIPDm accumulation due to decreased flow and/ or projection data acquired during a single continuous 3600 rotation. pH in the region of the neoplasm as well as in the associated The data were also reformatted into longitudinal sections. An inter­ vasogenic edema and overlying gray matter. nal first-order attenuation correction was applied to the data during the reconstruction to compensate for the effects of gamma ray attenuation. In addition to a visual analysis of the hard film copy, Since th e initial applicati on of xenon-1 33 s.tudies in man [1 , 2], regions of interest (ROI) were selected for computing counts/ voxel new techniques have been sought to characteri ze reg ional cerebral and ultimately rCBF. blood fl ow (rCBF) with improved morphologic specific ity. The non­ rad ioacti ve xenon-transmi ssion computed tomographic (CT) Isotope Preparation method [3] provides excell ent anatomi c resolution but is somewhat cumbersome due to the stringent requirements of the gas-breathing N ,N, N '-trimethyl-N '-(2-hydroxyl-3-methyl-5-iodobenzyl)-1 ,3-pro­ apparatus, particularly if end-tidal xenon concentration is to accu­ panediamine , HCI (HIPDm) (fig. 1) was synthesized and prepared in rately refl ect the arterial input function. Oxygen-15 techniques kit form [13]. High-purity, no-carrier-added iodine-1 23 (T'h = 13 .3 using positron emission tomography (PET) require a costly on-site hr) was made by the 127 1(P,5n) ' 23 Xe_'231 reaction (Crocker Nuclear cyclotron and chemistry laboratory [4]. Laboratory, University of California at Davis). The radiochemical New approaches are th erefore being expl ored to use th e far less purity of the labeled HIPDm was greater than 93% and the dose of costl y and more widely accessible technique of single-photon emis­ iodine-123 was 10-14 mCi (370-519 MBq) for animal studies and sion computed tomography (SPECT) in conjuncti on with diffu sible 5-6 mCi (185-222 MBq) for patients. in ert gasses [5] or new classes of iodine-1 23-labeled radiotracers [6-12]. This study describes the validati on of rCBF measurements HIPDm Characterization calculated using one of th ese iodine-123-labeled radiopharmaceu­ ti cals, hydroxyiodopropyldiamine (HIPDm) [1 3]. We are thus at­ The first pass fraction of 1231_H IPDm extracted by brain tissue tempting to determine wheth er rCBF in ml 100 g - I min - I can be was estimated after a bolu s infusion of the radiotracer into th e determined accurately and reproducibly in li ving subjects. Although internal carotid artery and the monitoring of the initial time activity 'Department of Radiology, Box 3808, Duke University Medical Center, Durham, NC 27710. Address reprint requests to B. P. Drayer. ' Department of Neurology, Duke University Medical Center, Durham, NC 277 10. ' Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710. ' Department of Nuclear Medicine, Veterans Administration Medical Center, Buffalo, NY 142 15. AJNR 4:572-576, May / June 1983 0195- 6108 / 83/ 0403-0572 $00.00 © Am erican Roentgen Ray Society AJNR :4, May/June 1983 PET AND RADIONUCLIDE STUDIES 5 73 curve from consecutive 1 sec collections using a gamma camera. activity of 123 1_HIPDm in a se lected ROI from the SPECT scans in Th e retention of 1231_HIPDm acti vity in th e brain was analyzed usin g counts sec- I g - I, and Ca th e total acti vi ty by well-counting in an three 26 min SPECT scans obtained in the 8-34 , 40-66, and 100- arteri al bl ood sample constantly withdrawn over the immediate 5 126 min intervals after the intracarotid or intravenous administration min of radiotracer infusion minus the acti vity in a 5 min sampl e of thp radiotracer. All baboon (Papio cynocephalus ) studies were begun 10 min after infusion in counts sec- I. A calibrati on factor to performed in an intubaled animal using intravenous sodium pento­ convert well-counter acti vity to SPECT unit acti vity is deri ved by barbital anesthesia. The CO2 concentration in the arteri al blood was well-counting and SPECT-scann ing the blood. " Arteri ali zed " ve­ in the 35-45 torr range. nous bl ood [17, 18] was drawn from a hand vein aft er warming to 44°C in a speciall y designed hand warm er for human stu dies. Brair acti vity from chosen ROls (Ci) was obtain ed from the 8-34, 40-66, Cerebral Blood Flow Analysis and 100-1 26 min SPECT scans. In order to compensate for finite resolution and partial vo lume averag ing affecting the mean acti vity If a close correspondence exists between the derived rCBF as in the se lected gray or white matter ROI, we used a simulated brain determined by carbonized microspheres and HIPDm, the straight­ phantom containing proportional concentrati ons of iodine-123. forward flow equation based on organ deposition and arterial input To determine the reproducibility of the SPE CT - HIPDm method, sampling [16] can be used for in vivo HIPDm (" metabolic micro­ the same normal baboon was studied three times at weekly inter­ sphere" ) studies: F = (WCi/ Ca) x 100, where F is the rCBF in ml 1 1 vals. This same animal was stu died again 2 weeks later while 100 g - I min- , W the constant withdrawal rate in ml min - , Ci the diffusely encephalopathic foll owin g a retroorbital craniotomy and resultinq subarachnoid hemorrhage. After clinical recovery, a fifth study was perform ed on this an imal 2 days after li gati on of the left middl E. c:e rebral artery producing focal cerebral infarcti on with neu­ HO rologic symptomatology. In order to verify the use of the microsphere paradigm for HIPDm studies, scandium-46 microspheres and iodine-125 HIPDm were injec ted via a catheter into the left ventricle of th e heart in th e calf. The animals were kill ed at 30 min foll owed by excision of multiple small secti ons of gray and white matter for well-counting. In addi­ ti on, arteri al blood was drawn at a constant rate over the 0-5 and 10-1 5 min time intervals. Thick-secti on autoradiographs were also prepared from 1 2-mm-thick coronal brain secti ons to correspond Fig. 1 .-N,N,N'-trimethyl-N'-(2-hydroxyl-3-m ethyl-5-iodobenzyl)-1 ,3-pro­ to th e SPECT sli ce thickness. panediamine· HCI(HIPDm). Human Studies Four pati ents with gli oma were studied after the infusion of 5- 6 mCi (1 85- 222 MBq) of HIPDm. The Ca was determined from arteri alized ve nous bl ood withdrawn at a constant rate and the Ci from chosen ROls (25 x 25 mm) on the SPECT scans. All patients had an intravenously enhanced CT study perform ed to determine tumor localizati on, blood-brain barrier integrity , and extent of va­ sogenic edema. A SPECT scan was also obtained to analyze blood­ brain barrier integrity using 99m Tc-glucoheptonate and compared with the SPECT-HIPDm rCBF study. Results Fig. 2._ 1251_HIPDm autoradiography. A 12-mm­ Extraction and Retention thick coronal autoradiographic section of cow brain confirms that >25 1_HIPDm distribution in brain (gray > In addition to the brain , the major uptake of HIPDm occurs in th e white> cerebrospinal fluid) is proportional to rCBF. lungs. No significant acti vity was seen in the eyes. The first pass Fig. 3 .-Cerebral infarction in a ba­ boon 48 hr after surgical ligation of mid­ dle cerebral artery (MCA) resulted in profound contralateral hemiparesis, hemianesthesia, and homonymous hem­ ianopsia. A, CT. Large area of de­ creased density in distribution of ligated MCA.
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