Asia Oceania Journal of Nuclear Medicine and Biology

Asia Oceania Journal of Nuclear Medicine and Biology

A non-invasive, reference region-based method for quantification of cerebral blood flow and oxygen metabolism using oxygen-15 labeled gases and positron emission tomography

Document Type : Original Article

Authors
Hiroshi Ito 1, 2
Masanobu Ibaraki 3
Ryo Yamakuni 1
Naoyuki Ukon 2
Shiro Ishii 1
Kenji Fukushima 1
Hitoshi Kubo 2, 4
Kazuhiro Takahashi 2
1 Department of Radiology and Nuclear Medicine, Fukushima Medical University, Fukushima, Japan
2 Advanced Clinical Research Center, Fukushima Medical University, Fukushima, Japan
3 Department of Radiology and Nuclear Medicine, Akita Research Institute of Brain and Blood Vessels, Akita, Japan
4 Department of Radiological Sciences, School of Health Sciences, Fukushima Medical University, Fukushima, Japan
10.22038/aojnmb.2025.81433.1578
Abstract
Objective(s): Measurement of cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) by positron emission tomography (PET) with oxygen-15 labeled gases is widely used for investigation into the pathophysiology of occlusive cerebrovascular disease. However, all methods for quantification of CBF, CBV, OEF, and CMRO2 by PET with oxygen-15 labeled gases require invasive arterial blood sampling. The present study developed a reference region-based method for quantification of CBF, CBV, OEF, and CMRO2 using PET and oxygen-15 labeled gases based on the steady-state method without invasive arterial blood sampling.
Methods: The CBF, CBV, OEF, and CMRO2 were measured in patients with occlusive cerebrovascular disease by PET using 15O-labeled gases, C15O2, C15O, and 15O2, with the steady-state method. In the present method, the ratios of values in a brain region to the reference region for CBF, CBV, OEF, and CMRO2 were calculated without invasive arterial blood sampling.
Results: Good correlations were observed for the ratios of values of the cerebral lesion to the reference brain region for CBF, CBV, OEF, and CMRO2 calculated by the present method as compared with those obtained by the steady-state method with arterial blood sampling, indicating its validity. Simulation studies showed that errors in estimated values calculated by the present method were negligibly small for both conditions of misery perfusion and matched hypoperfusion.
Conclusion: A simple method for noninvasive quantification of CBF, CBV, OEF, and CMRO2 using PET and oxygen-15 labeled gases could be developed based on the steady-state method. This method can be used to investigate the pathophysiology of occlusive cerebrovascular disease.  
Keywords
Brain
CBF
CMRO2
OEF
PET
Subjects
  1. Gibbs JM, Wise RJ, Leenders KL, Jones T. Evaluation of cerebral perfusion reserve in patients with carotid-artery occlusion. Lancet. 1984; 1(8372): 310-4.
  2. Powers WJ, Grubb RL, Raichle ME. Physiological responses to focal cerebral ischemia in humans. Ann Neurol. 1984; 16(5): 546-52.
  3. Powers WJ, Grubb RL, Darriet D, Raichle ME. Cerebral blood flow and cerebral metabolic rate of oxygen requirements for cerebral function and viability in humans. J Cereb Blood Flow Metab. 1985; 5(4): 600-8.
  4. Leblanc R, Yamamoto YL, Tyler JL, Diksic M, Hakim A. Borderzone ischemia. Ann Neurol. 1987; 22(6):707-13.
  5. Kanno I, Uemura K, Higano S, Murakami M, Iida H, Miura S, et al. Oxygen extraction fraction at maximally vasodilated tissue in the ischemic brain estimated from the regional CO2 responsiveness measured by positron emission tomography. J Cereb Blood Flow Metab. 1988; 8(2): 227-35.
  6. Sette G, Baron JC, Mazoyer B, Levasseur M, Pappata S, Crouzel C. Local brain haemo-dynamics and oxygen metabolism in cerebrovascular disease. Positron emission tomography. Brain. 1989; 112(Pt 4): 931-51.
  7. Yamauchi H, Fukuyama H, Kimura J, Konishi J, Kameyama M. Hemodynamics in internal carotid artery occlusion examined by positron emission tomography. Stroke. 1990; 21(10):1400-6.
  8. Okazawa H, Kudo T. Clinical impact of hemodynamic parameter measurement for cerebrovascular disease using positron emission tomography and 15O-labeled tracers. Ann Nucl Med. 2009; 23(3): 217-27.
  9. Ogasawara K, Ito H, Sasoh M, Okuguchi T, Kobayashi M, Yukawa H, et al. Quantitative measurement of regional cerebrovascular reactivity to acetazolamide using 123I-N-isopropyl-p-iodoamphetamine autoradio-graphy with SPECT: validation study using H215O with PET. J Nucl Med. 2003; 44(4): 520-5.
  10. Ito H, Inoue K, Goto R, Kinomura S, Sato T, Kaneta T, et al. Error analysis of measured cerebral vascular response to acetazolamide stress by I-123-IMP autoradiographic method with single photon emission computed tomography: errors due to distribution volume of I-123-IMP. Ann Nucl Med. 2004; 18(3): 221-6.
  11. Derdeyn CP, Grubb RL, Jr., Powers WJ. Cerebral hemodynamic impairment: methods of measurement and association with stroke risk. Neurology. 1999; 53(2): 251-9.
  12. Everett BA, Oquendo MA, Abi-Dargham A, Nobler MS, Devanand DP, Lisanby SH, et al. Safety of radial arterial catheterization in PET research subjects. J Nucl Med. 2009; 50(10): 1742.
  13. Iguchi S, Hori Y, Moriguchi T, Morita N, Yamamoto A, Koshino K, et al. Verification of a semi-automated MRI-guided technique for non-invasive determination of the arterial input function in 15O-labeled gaseous PET. Nucl Instrum Methods Phys Res A. 2013; 702: 111-3.
  14. Su Y, Vlassenko AG, Couture LE, Benzinger TL, Snyder AZ, Derdeyn CP, et al. Quantitative hemodynamic PET imaging using image-derived arterial input function and a PET/MR hybrid scanner. J Cereb Blood Flow Metab. 2017; 37(4): 1435-46.
  15. Kudomi N, Maeda Y, Yamamoto H, Yamamoto Y, Hatakeyama T, Nishiyama Y. Reconstruction of input functions from a dynamic PET image with sequential administration of 15O2 and [Formula: see text] for noninvasive and ultra-rapid measurement of CBF, OEF, and CMRO2. J Cereb Blood Flow Metab. 2018; 38(5): 780-92.
  16. Van der Weijden CWJ, Mossel P, Bartels AL, Dierckx R, Luurtsema G, Lammertsma AA, et al. Non-invasive kinetic modelling approaches for quantitative analysis of brain PET studies. Eur J Nucl Med Mol Imaging. 2023; 50(6): 1636-50.
  17. Frackowiak RS, Lenzi GL, Jones T, Heather JD. Quantitative measurement of regional cerebral blood flow and oxygen metabolism in man using 15O and positron emission tomography: theory, procedure, and normal values. J Comput Assist Tomogr. 1980; 4(6): 727-36.
  18. Ito H, Kanno I, Kato C, Sasaki T, Ishii K, Ouchi Y, et al. Database of normal human cerebral blood flow, cerebral blood volume, cerebral oxygen extraction fraction and cerebral metabolic rate of oxygen measured by positron emission tomography with 15O-labelled carbon dioxide or water, carbon monoxide and oxygen: a multicentre study in Japan. Eur J Nucl Med Mol Imaging. 2004; 31(5): 635-43.
  19. Derdeyn CP, Videen TO, Simmons NR, Yundt KD, Fritsch SM, Grubb RL, Jr., et al. Count-based PET method for predicting ischemic stroke in patients with symptomatic carotid arterial occlusion. Radiology. 1999; 212(2): 499-506.
  20. Ibaraki M, Shimosegawa E, Miura S, Takahashi K, Ito H, Kanno I, et al. PET measurements of CBF, OEF, and CMRO2 without arterial sampling in hyperacute ischemic stroke: method and error analysis. Ann Nucl Med. 2004; 18(1): 35-44.
  21. Kobayashi M, Okazawa H, Tsuchida T, Kawai K, Fujibayashi Y, Yonekura Y. Diagnosis of misery perfusion using noninvasive 15O-gas PET. J Nucl Med. 2006; 47(10): 1581-6.
  22. Ito H, Kubo H, Takahashi K, Nishijima KI, Ukon N, Nemoto A, et al. Integrated PET/MRI scanner with oxygen-15 labeled gases for quantification of cerebral blood flow, cerebral blood volume, cerebral oxygen extraction fraction and cerebral metabolic rate of oxygen. Ann Nucl Med. 2021; 35(4): 421-8.
  23. Phelps ME, Huang SC, Hoffman EJ, Kuhl DE. Validation of tomographic measurement of cerebral blood volume with C-11-labeled carboxyhemoglobin. J Nucl Med. 1979; 20(4): 328-34.
  24. Martin WR, Powers WJ, Raichle ME. Cerebral blood volume measured with inhaled C15O and positron emission tomography. J Cereb Blood Flow Metab. 1987; 7(4): 421-6.
  25. Iida H, Jones T, Miura S. Modeling approach to eliminate the need to separate arterial plasma in oxygen-15 inhalation positron emission tomography. J Nucl Med. 1993; 34(8): 1333-40.
  26. Lammertsma AA, Jones T. Correction for the presence of intravascular oxygen-15 in the steady- state technique for measuring regional oxygen extraction ratio in the brain: 1. description of the method. J Cereb Blood Flow Metab. 1983; 3(4): 416-24.
  27. Lammertsma AA, Baron JC, Jones T. Correction for intravascular activity in the oxygen-15 steady-state technique is independent of the regional hematocrit. J Cereb Blood Flow Metab. 1987; 7(3): 372-4.
  28. Delso G, Furst S, Jakoby B, Ladebeck R, Ganter C, Nekolla SG, et al. Performance measurements of the Siemens mMR integrated whole-body PET/MR scanner. J Nucl Med. 2011; 52(12): 1914-22.
  29. Watson CC, Newport D, Casey ME. A single scatter simulation technique for scatter correction in 3D PET. In: Grangeat P, Amans JL, editors. Three-dimensional image reconstruction in radiology and nuclear medicine. Dordrecht, the Netherlands: Kluwer Academic Publishers; 1996. p. 255-68.
  30. Burnett RW, Noonan DC. Calculations and correction factors used in determination of blood pH and blood gases. Clin Chem. 1974; 20(12): 1499-506.
  31. Dickson JC, O'Meara C, Barnes A. A comparison of CT- and MR-based attenuation correction in neurological PET. Eur J Nucl Med Mol Imaging. 2014; 41(6): 1176-89.
  32. Kuroda S, Shiga T, Ishikawa T, Houkin K, Narita T, Katoh C, et al. Reduced blood flow and preserved vasoreactivity characterize oxygen hypometabolism due to incomplete infarction in occlusive carotid artery diseases. J Nucl Med. 2004; 45(6): 943-9.
  33. Ito H, Kanno I, Shimosegawa E, Tamura H, Okane K, Hatazawa J. Hemodynamic changes during neural deactivation in human brain: a positron emission tomography study of crossed cerebellar diaschisis. Ann Nucl Med. 2002; 16(4): 249-54.
Asia Oceania Journal of Nuclear Medicine and Biology
Volume 13, Issue 2
July 2025
Pages 126-137