Blood volume (VB) in tissue
The blood in the vascular volume fraction contributes to the total radioactivity concentration of the tissue measured by PET, and may need to be accounted for in the data analysis.
In PET data analysis, large blood vessels can be avoided by careful drawing of regions-of-interest (ROIs). Still the ROI will contain smaller arteries, venules and capillaries. Relatively poor image resolution or movement may also lead to radioactivity spillover from adjacent blood pools to the ROI, especially in heart studies.
Due to the vascular volume fraction, VB, the apparent regional (or voxel) time-activity curve, CPET(t), that is measured by PET is a weighted sum of 'pure' tissue time-activity, CT(t), and blood curve, CB(t):
Published values for VB
Normal vascular volume fraction for the brain grey matter is 5.2 ± 1.4 %, for white matter 2.7 ± 0.6 %, and for cerebellum 4.7 ± 2.0 %, as measured using [15O]CO PET (Leenders et al., 1990); a ratio of 0.85 for small vessel versus large vessel hematocrit was used in this study. Blood volume in grey and white matter was found to decrease with age approximately 0.50 % per year (Leenders et al., 1990). Using [11C]CO, Muzi et al., 2009 measured average VB for the brain to be 0.044 mL/g, with range 0.037-0.055 mL/g.
Blood volume can change during hypercapnia and hypocapnia, from 5.5 ± 0.6 % to 6.9 ± 1.2 and 5.1 ± 0.8 %, respectively, in cortical grey matter, and from 2.1 ± 0.5 % to 2.8 ± 0.8 and 2.0 ± 0.5 % in central white matter (Rostrup et al 2005). Changes in blood volume generally are smaller than changes in blood flow (Ito et al., 2003).
Blood volume may be lower in central grey matter (4.2 ± 1.0 %) than in cortical grey matter (Rostrup et al 2005).
The regional intracapillary myocardial blood volume in humans (six CAD patients) has been measured to be 12.9% (Wacker et al. 2002). This represents almost the entire intramyocardial blood volume (about 90%) because of the relatively low arterial and venous (about 5%) vascular volumes in myocardium (Wacker and Bauer, 2003). Thus, we can estimate that the total vascular volume is about 14%.
Arterial fraction (fA) of blood volume
In full kinetic modelling, the vascular volume in the tissue volume must be taken into consideration. Sometimes, it is even necessary to separate the arterial and venous volumes of tissue vasculature.
Venous cerebral blood volume changes are much less (approximately 50%) than arterial blood volume changes (Schaller 2004). Arterial or arterial and capillary blood volumes (Va or V0), can be estimated as one of the compartment model parameters from dynamic [15O]H2O or [15O]O2 studies, and those have even been considered to be more reliable hemodynamic parameters reflecting changes in cerebral arterial blood volume than VB (CBV) estimated from [15O]CO study (Okazawa et al 2001). This may be the reason that CBF-to-CBV ratio, based on steady-state [15O]CO2 and [15O]CO PET, may not optimally represent the local cerebral perfusion pressure (CPP).
Estimates of regional arterial and venous blood volume fractions
Arterial fraction of cerebral blood volume in humans has been estimated using PET to be about 30 % (Ito et al., 2001). This is in line with the MRI measurement where the arterial blood volume fraction was found to be 29 ± 7 % in the total cerebral blood volume in the rat brain (Duong and Kim, 2000). This fraction is similar to that of the systemic circulation, but much higher than that (16 or 17 %) widely used for the measurement of cerebral metabolic rate of oxygen (CMRO2) using PET. The venous plus capillary fraction of cerebral blood volume was 63-70 % (Ito et al., 2001). Different PET and MRI studies have given variable results, but generally in the brain the arterial fraction seems to be 20-30% (Hua et al., 2019).
If VB is measured with [15O]CO scan or literature value is used, then it can be corrected before modelling (see below), or constrained in compartment model fitting. If it is not known, it should be fitted as one model parameter in the compartment model fitting to avoid bias in other parameter estimates; however, the model-derived estimate for VB can be affected by delay and dispersion of input curve, and thus not necessarily reliable for studying vascular volume.
Note that metabolite corrected plasma TAC should not be used to represent blood TAC, because that may lead to biased model parameter estimates, or misleading model structure with apparent additional tissue compartment (Lammertsma, 2002).
Note that the peak radioactivity concentration in venous blood is substantially lower than in arterial blood because of dispersion and extraction in capillaries. Since arterial fraction of cerebral blood volume in humans is ∼30% (Ito et al. 2001), the common assumption that arterial or venous blood curve represents total blood volume in tissue may lead to negative tissue concentrations during the blood peak and introduces a bias in results, if blood TAC is subtracted from tissue TACs based on total blood volume fraction. When VB is estimated as parameter in model fitting but venous blood TAC is not accounted for, that may lead to poor fit with one-tissue compartmental model, causing bias in model parameter estimates. The additional parameters of two-tissue compartmental model can compensate for the neglected venous blood, and because of that AIC and other model comparison techniques may support selection of two-tissue compartmental model over one-tissue compartmental model (Blomqvist et al., 1995).
Vascular volume fraction of blood in tissue can be measured with PET using carbon monoxide, labeled with either O-15 or C-11. The CO method is very simple: inhaled tracer dose of labelled carbon monoxide is assumed to bind and stay bound to haemoglobin in the blood. After the inhaled [15O]CO or [11C]CO has bound to the haemoglobin in circulating red blood cells, and the RBCs are distributed evenly in the vasculature of the whole body, the concentrations of radioactivity in tissue (using PET) and in blood (manual venous sampling) are measured. To get an estimate of the VB in tissue, the tissue radioactivity concentration (CPET) is divided by concentration in blood (CB). For precise quantitation, the difference between hematocrit values in tissue vasculature (small vessel hematocrit) and in large veins where blood sampling is done, must also be accounted for.
The blood volume as percentage of tissue volume can be calculated from equation
Human serum albumin (HSA) has been labelled with 68Ga, 62Cu and 64Cu, 11C, and 18F (Wagner & Welch, 1979; Turton et al., 1984; Fujibashi et al., 1990; Anderson et al., 1993; Chang et al., 2005; Hoffend et al., 2005; Mier et al., 2005; Wängler et al., 2009; Schiller et al., 2013; Basuli et al., 2015 and 2018; Jain et al., 2017). After bolus infusion, the radiotracer distributes evenly in the plasma space of the vasculature in the whole body, and VB can be measured as the ratio of radioactivity concentrations of tissue and blood, similarly as in carbon monoxide studies. Precision of the results depends on the in vivo stability of the radiotracer and its retention in the blood compartment. Tissue-to-blood ratio should not change during the scan. Due to the hepatobiliary clearance the results from the liver and intestine are not reliable. In addition, tissue-to-blood ratio in bone and muscle was varied markedly in a study by Jain et al., 2017.
Albumin can also be labelled in vivo using a pre-labelled albumin binder, such as Evans blue based [18F]AlF-NEB (Niu et al., 2014; Wang et al., 2015) and [68Ga]NEB (Zhang et al., 2015), [68Ga]ABY-028 (Jussing et al., 2020), and maleimide-based [68Ga]DM (Feng et al., 2022).
Any macromolecule that stays in circulation long enough to allow imaging can be used as a blood pool agent. For instance, hyperbranched polyglycerols (HPG) are biocompatible, non-toxic, with several hour half-life in circulation (Schmitt et al., 2018). In rat studies, [68Ga]HPG has been shown to be a promising blood pool agent for PET imaging (Saatchi et al., 2023).
Cardiac blood pool imaging
Unrelated to blood volume inside myocardial tissue, blood pool agents are used to assess cardiac output and ejection fraction.
- Measurement of blood volume using labelled CO
- Plasma protein binding
- Blood flow
- Vascular system
- Lymphatic system
- Compartmental model
- Modelling A-V difference
Eichling JO, Raichle ME, Grubb RL Jr, Larson KB, Ter-Pogossian MM. In vivo determination of cerebral blood volume with radioactive oxygen-15 in the monkey. Circ Res. 1975; 37: 707-714. doi: 10.1161/01.res.37.6.707
Gregersen MI, Rawson RA. Blood Volume. Physiol Rev. 1959; 39(2): 307-342. doi: 10.1152/physrev.19126.96.36.1997.
Ito H, Kanno I, Ibaraki M, Hatazawa J, Miura S. Changes in human cerebral blood flow and cerebral blood volume during hypercapnia and hypocapnia measured by positron emission tomography. J Cereb Blood Flow Metab. 2003; 665-670. doi: 10.1097/01.WCB.0000067721.64998.F5.
Ito H, Kanno I, Iida H, Hatazawa J, Shimosegawa E, Tamura H, Okudera T. Arterial fraction of cerebral blood volume in humans measured by positron emission tomography. Ann Nucl Med. 2001; 15: 111-116. doi: 10.1007/BF02988600.
Lammertsma AA, Brooks DJ, Beaney RP, Turton DR, Kensett MJ, Heather JD, Marshall J, Jones T. In vivo measurement of regional cerebral haematocrit using positron emission tomography. J Cereb Blood Flow Metab. 1984; 4: 317-322. doi: 10.1038/jcbfm.1984.47.
Lammertsma AA. Radioligand studies: imaging and quantitative analysis. Eur Neuropsychopharmacol. 2002; 12: 513-516. doi: 10.1016/S0924-977X(02)00100-1.
Leenders KL, Perani D, Lammertsma AA, Heather JD, Buckingham P, Healy MJR, Gibbs JM, Wise RJS, Hatazawa J, Herold S, Beaney RP, Brooks DJ, Spinks T, Rhodes C, Frackowiak RSJ, Jones T. Cerebral blood flow, blood volume and oxygen utilization. Normal values and effect of age. Brain 1990; 113: 27-47. doi: 10.1093/brain/113.1.27.
Manzone TA, Dam HQ, Soltis D, Sagar VV. Blood volume analysis: a new technique and new clinical interest reinvigorate a classic study. J Nucl Med Technol. 2007; 35: 55-63. doi: 10.2967/jnmt.106.035972.
Martin WRW, Powers WJ, Raichle ME. Cerebral blood volume measured with inhaled C15O and positron emission tomography. J Cereb Blood Flow Metab. 1987; 7: 421-426. doi: 10.1038/jcbfm.1987.85.
Okazawa H, Yamauchi H, Sugimoto K, Toyoda H, Kishibe Y, Takahashi M. Effects of acetazolamide on cerebral blood flow, blood volume, and oxygen metabolism: a positron emission tomography study with healthy volunteers. J Cereb Blood Flow Metab. 2001; 21: 1472-1479. doi: 10.1097/00004647-200112000-00012.
Rostrup E, Knudsen GM, Law I, Holm S, Larsson HBW, Paulson OB. The relationship between cerebral blood flow and volume in humans. Neuroimage 2005; 24: 1-11. doi: 10.1016/j.neuroimage.2004.09.043.
Schaller B. Physiology of cerebral venous blood flow: from experimental data in animals to normal function in humans. Brain Res Rev. 2004; 46: 243-260. doi: 10.1016/j.brainresrev.2004.04.005.
Wagner SJ, Welch MJ. Gallium-68 labeling of albumin and albumin microspheres. J Nucl Med. 1979; 20(5): 428-433. PMID: 120419.
Updated at: 2023-03-08
Written by: Vesa Oikonen