Abstract
As a result of the limited spatial resolution of positron emission tomographic scanners, the measurements of physiological parameters are compromised by tissue heterogeneity. The effect of tissue heterogeneity on a number of parameters was studied by simulation and an analytical method. Five common tracer models were assessed. The input and tissue response functions were assumed to be free from noise and systematic errors. The kinetic model was assumed to be perfect. Two components with different kinetics were mixed in different proportions and contrast with respect to the model parameters. Different experimental protocols were investigated. Of three methods investigated for the measurement of cerebral blood flow (CBF) (steady state, dynamic, integral), the second one was least sensitive to errors caused by tissue heterogeneity and the main effect was an underestimation of the distribution volume. With the steady state method, errors in oxygen extraction fraction caused by tissue heterogeneity were always found to be less than the corresponding errors in CBF. For myocardial blood flow the steady state method was found to perform better than the bolus method. The net accumulation of substrate (i.e. rCMRgjc in the case of glucose analogs) was found to be comparatively insensitive to tissue heterogeneity. Individual rate constants such ask 2 andk 3 for efflux and metabolism of the substrate in the pool of unmetabolized substrate in the tissue, respectively, were found to be more sensitive. In studies of radioligand binding, using only tracer doses, the effect of tissue heterogeneity on the parameterk on ·B max could be considerable. In studies of radioligand binding using a protocol with two experiments, one with high and one with low specific activity,B max was found to be insensitive whileK d was very sensitive to tissue heterogeneity.
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Phelps ME, Huang SC, Hoffman EJ, Kuhl DE. Validation of tomographic measurement of cerebral blood volume with C11-labeled carboxyhemoglobin.J Nucl Med 1979; 20: 328–334.
Patlak CS, Blasberg R, Fenstermacher J. Graphical evaluation of blood-to-brain transfer constants from multiple time uptake data.J Cereb Blood Flow Metab 1983; 3: 1–7.
Herholz K, Patlak CS. The influence of tissue heterogeneity on results of fitting nonlinear model equations to regional tracer uptake curves: with an application to Compartmental models used in positron emission tomography.J Cereb Blood Flow Metab 1987; 7: 214–229.
Coxson PG, Salmeron EM, Huesman RH, Mazoyer BM. Simulation of compartmental models for kinetic data from a positron emission tomograph.Comput Methods Programs Biomed 1992;37: 205–214.
Beck JV, Arnold KJ. Parameter estimation in engineering and science. New York: John Wiley, Chap. 7.
James F, Roos M. MINUIT.Comput Phys Commun 1975; 10: 343–367.
Frackowiak RSJ, Lenzi GL, Jones T, Heather JD. Quantitative measurement of regional cerebral blood flow and oxygen metabolism in man using15O and positron emission tomography: theory, procedure and normal values.J Comput Assist Tomogr 1980; 4: 727–736.
Koeppe RA, Holden JE, Ip WR. Performance comparison of parameter estimation techniques for the quantitation of local cerebral blood flow by dynamic positron computed tomography.J Cereb Blood Flow Metab 1985; 5: 224–234.
Ginsberg MD, Lockwood AH, Busto R, Finn RD, Butler CM, Cendan IE, Goddard J. A simplified in vivo autoradiographic strategy for the determination of regional cerebral blood flow by positron emission tomography: theoretical considerations and validation studies in the rat.J Cereb Blood Flow Metab 1982; 2: 89–98.
Raichle ME, Martin WRW, Herscovitch P, Mintun MA, Markham J. Brain blood flow measured with intravenous H2 150. II. Implementation and validation.J Nucl Med 1983; 24: 790–798.
Lammertsma AA, Jones T. Low oxygen extraction fraction in tumors measured with the oxygen-15 steady state technique: effect of tissue heterogeneity.Br J Radiol 1992; 65: 697–700.
Iida H, Kanno I, Takahashi A. Measurement of absolute myocardial blood flow with H2O15 and dynamic positron emission tomography. Strategy for quantification in relation to the partial-volume effect.Circulation 1988; 78: 104–115.
Bergmann SR, Herrero P, Markham J. Noninvasive quantitation of myocardial blood flow in human subjects with oxygen15-labeled water and positron emission tomography.J Am Coll Cardiol 1989; 14: 639–652.
Araujo LI, Lammertsma AA, Rhodes CG, McFalls EQ, Iida H, Rechavia E, Galassi A, De Silva R, Jones T, Maseri A. Noninvasive quantification of regional myocardial blood flow in coronary artery disease with oxygen-15-labeled carbon dioxide inhalation and positron emission tomography.Circulation 1991; 83: 875–885.
Lammertsma AA, De Silva R, Araujo LI, Jones T. Measurement of regional myocardial blood flow using C15O2 and positron emission tomography: comparison of tracer models.Clin Phys Physiol Meas 1992; 13: 1–20.
Lammertsma AA, Mazoyer BM. EEC concerted action on cellular degeneration and regeneration studied with PET: modelling expert meeting blood flow measurement with PET.Eur J Nucl Med 1990: 16: 807–812.
Mazoyer BM, Trebossen RT, Schoukroun C, Verrey B, Syrota A, Vacher J, Lemasson P, Monnet O, Bouvier A, Lecomte IL. Physical characteristics of TTV03, a new high spatial resolution time-of-flight positron tomograph.IEEE Trans Nucl Sci 1985; 37: 778–782.
Feinendegen LE, Herzog H, Wieler H, Patton DD, Schmid A. Glucose transport and utilization in the human brain: model using carbon-11 methyl glucose and positron emission tomography.J Nucl Med 1986; 27: 1867–1877.
Lammertsma AA, Jones T. Correction of the presence of intravascular oxygen-15 in the steady-state techniques for measuring regional oxygen extraction ratio in the brain. 1. Description of the method.J Cereb Blood Flow Metab 1983; 3: 416–424.
Phelps ME, Huang SC, Hoffman EJ, Selin C, Sokoloff L, Kuhl DE. Tomographic measurement of local cerebral glucose metabolic rate in humans with (F18)2-fluoro-2-deoxy-D-glucose: validation of method.Ann Neurol 1979; 6: 371–388.
Blomqvist G, Stone-Elander S, Halldin C, Roland P, Widén L, Lindqvist M, Swahn C-G, Långström B, Wiesel FA. Positron emission tomographic measurement of cerebral glucose utilization using [1-11C]D-glucose.J Cereb Blood Flow Metab 1990; 10: 467–483.
Bahn MM, Huang SC, Hawkins RA, Satyamurthy N, Hoffman JM, Barrio JR, Mazziotta JC, Phelps ME. Models for in vivo kinetic interactions of dopamine D2-receptors and 3-(2′[18F]fluoroethyl)spiper,one examined with positron emission tomography.J Cereb Blood Flow Metab 1989; 9: 840–849.
Wienhard K, Coenen HH, Pawlik G, Rudolf J, Laufer P, Jovkar S, Stöcklin G, Heiss WD. PET studies of dopamine receptor distribution using [18F]fluoroethylspiperone: findings in disorders related to dopaminergic system.J Neural Transm Gen Sect 1990; 81: 195–213.
Lammertsma AA, Bench CJ, Price GW, Cremer JE, Luthra SK, Turton D, Wood ND, Frackowiak RSJ. Measurement of cerebral monoamine oxidase B activity usingL-[11C]deprenyl and dynamic positron emission tomography.J Cereb Blood Flow Metab 1991; 11: 545–556.
Bustany P, Sargent T, Saudubray JM, Henry IF, Comar D. Regional human brain uptake and protein incorporation of [11C]L-methionine studied in vivo with PET.J Cereb Blood Flow Metab (Suppl) 1981; 1: S17-S18.
Wienhard K, Herholz K, Coenen HH, Rudolf J, Kling P, Stöcklin G, Heiss WD. Increased amino acid transport into brain tumors measured by PET ofL-(2-18F)Fluorotyrosine.J Nucl Med 1991; 32: 1338–1346.
Huang SC, Barrio JR, Phelps ME. Neuroreceptor assay with positron emission tomography: equilibrium versus dynamic approaches.J Cereb Blood Flow Metab 1986; 6: 515–521.
Maziére B, Loch C, Baron JC, Sgouropoulos P, Duquesnoy N, D'Antona R, Cambon H. In vivo quantitative imaging of dopamine receptors in human brain using positron emission tomography and [86Br]bromospiperone.Eur J Pharmacol 1985; 114: 267–272.
Arnett CD, Wold AP, Shine CY, Fowler IS, McGregor RR, Christman DR, Smith MR. Improved delineation of human dopamine receptors using [18F]-N-methylspiroperidol and PET.J Nucl Med 1986; 27: 1878–1882.
Wong DF, Gjedde A, Wagner HN Jr. Quantification of neuroreceptors in the living human brain. I. Irreversibvle binding of ligands.J Cereb Blood Flow Metab 1986; 6: 137–146.
Barrio JR, Satyamurthy N, Huang SC, Keen RE, Nissenson CHK, Hoffman JM, Ackerman RF, Bahn MM, Mazziotta JC, Phelps ME. 3-(2′-[18F]fluoroethyl)spiperone: in vivo biochemical and kinetic characterization in rodents, nonhuman primates, and humans.J Cereb Blood Flow Metab 1989; 9: 830–839.
Farde L, Hall H, Ehrin H, Sedvall G. Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET.Science 1986; 231: 258–261.
Lammertsma AA, Cunningham VJ, Deiber MP, Hether JD, Bloomfield PM, Nutt J, Frackowiak RSJ, Jones T. Combination of dynamic and integral methods for generating reproducible functional CBF images.J Cereb Blood Flow Metab 1990; 10: 675–686.
Gjedde A, Wienhard K, Heiss WD, Kloster G, Diemer NH, Herholz K, Pawlik G. Comparative regional analysis of 2-fluorodeoxyglucose and methylglucose uptake in brain of four stroke patients. With special reference to the regional estimation of the lumped constant.J Cereb Blood Flow Metab 1985; 5: 163–178.
Wienhard K, Pawlik G, Herholz K, Wagner R, Heiss WD. Estimation of local cerebral glucose utilization by positron emission tomography of [18F]2-fluoro-2-deoxy-D-glucose: a critical appraisal of optimization procedures.J Cereb Blood Flow Metab 1985; 5: 115–125.
Lammertsma AA, Brooks DJ, Frackowiak RSJ, Beaney RP, Herold S, Heather JD, Palmer AJ, Jones T. Measurement of glucose utilization with [18F]2-fluoro-2-deoxy-D-glucose: a comparison of different analytical methods.J Cereb Blood Flow Metab 1987; 7: 161–172.
Schmidt K, Mies G, Sokoloff L. Model of kinetic behavior of deoxyglucose in heterogeneous tissues in brain: a reinterpretation of the significance of parameters fitted to homogeneous tissue models.J Cereb Blood Flow Metab 1991; 11: 10–24.
Schmidt K, Lucignani G, Moresco RM, Rizzo G, Gilardi MC, Messa C, Colombo F, Fazio F, Sokoloff L. Errors introduced by tissue heterogeneity in estimation of local cerebral glucose utilization with current kinetic models of the [18F]fluorodeoxyglucose method.J Cereb Blood Flow Metab 1992; 12: 823–824.
Lucignani G, Schmidt KC, Moresco RM, Striano G, Colombo F, Sokoloff L, Fazio F. Measurement of regional cerebral glucose utilization with fluorine-18-FDG in PET in heterogeneous tissues: theoretical considerations and practical procedure.J Nucl Med 1993; 34: 360–369.
Blomqvist G, Pauli S, Farde L, Eriksson L, Persson A, Halldin C. Maps of receptor binding parameters in the human brain — a kinetic analysis of PET measurements.Eur J Nucl Med 1990; 16: 257–265.
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Blomqvist, G., Lammertsma, A.A., Mazoyer, B. et al. Effect of tissue heterogeneity on quantification in positron emission tomography. Eur J Nucl Med 22, 652–663 (1995). https://doi.org/10.1007/BF01254567
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DOI: https://doi.org/10.1007/BF01254567