New Contrast Agent/Tracer in Perfusion Imaging?
Thomas Christen1

1Stanford University, United States


The vast majority of perfusion MR approaches require the injection of a gadolinium based contrast agent or the magnetic labeling of arterial spins. Yet, other types of contrasts or tracers have also been proposed to probe the micro or macro vascular network. This lecture will present recent perfusion techniques based on the use of (1) iron oxide particles, (2) spontaneous or challenge-based BOLD contrast fluctuations, and (3) hyperpolarized compounds. These methods can offer high SNR, short acquisition times, and provide access to new biophysical markers such as microvessel geometry, hematocrit and blood oxygenation.


The vast majority of perfusion studies are conducted with either an exogenous gadolinium based contrast agent (DSC or DCE techniques) or endogenous contrasts from the magnetization of water protons in the arterial blood stream (ASL techniques). These methods provide measurements related to the vascular physiology, such as blood flow, blood volume, arterial transit time, and capillary permeability. Yet, other types of contrasts or tracers have also been proposed to probe the micro or macro vascular network. Iron oxide particles, spontaneous or challenge-based BOLD contrast fluctuations, and hyperpolarized compounds (amongst others) can lead to high SNR acquisitions, short acquisition times, and provide access to new biophysical markers such as microvessel geometry, hematocrit and blood oxygenation.

Iron oxide particles

Ultra-small super-paramagnetic iron oxide (USPIO) particles have been used for many years as MR contrast agents in small animal studies (1) (2) and have recently become available for human experiments (3) (4), agents used off label). They provide a strong T2* MR contrast mechanism which alters the MR signal in relation to the blood volume. Thus, these agents can offer high SNR in dynamic acquisitions and enhance spin-echo imaging (microvascular perfusion). Because of their small diameters, the particles are not rapidly cleared by the reticuloendothelial system and, therefore, have long blood plasma half-lives (>12h). They provide opportunities for high-resolution steady-state perfusion acquisitions (5) and measurements of microvessel geometry and blood oxygen saturation (6). Less known is the strong T1 relaxivity of some iron oxide agents, which allows ultra-high resolution angiography/venography acquisitions (~250microns in human brain).

BOLD contrast

The Blood Oxygen Level Dependent (BOLD) contrast is an obvious candidate for perfusion imaging techniques. It relies on the difference of magnetic susceptibility between oxyhemoglobin and deoxyhemoglobin and thus, is related to blood oxygenation, blood volume and blood flow (7). BOLD imaging is noninvasive and can be performed with high temporal and spatial resolution. The major difficulty is to disentangle the various contributions to the signal and to reduce artifacts such as field inhomogeneity and T2 variations. This can be achieved by observing the spatial and temporal variations of the BOLD signal in response to an external stimulus. The applied stimulus typically affects O2 directly (such as 100% oxygen gas inhalation) or indirectly through the strong CO2 effects on brain hemodynamics (such as carbogen [95% O2, 5% CO2] gas inhalation, breathhold, and acetazolamide). Results from gas challenges experiments can be used to calibrate the BOLD signal and obtain quantitative variations of the cerebral metabolic rate of O2 (CMRO2) as well as quantitative maps of blood volume and vessel size (8)(9)(10). Recent studies have demonstrated that the spontaneous fluctuations of the BOLD signal (similar to a resting-state fMRI exams) also provide information about cerebral reactivity and arterial arrival time (MTT, Tmax) without the need for exogenous contrast agents (11)(12)(13). Finally, direct blood relaxometry measurements (R1, R2, R2’) have been linked to local blood oxygenation and hematocrit measurements (14)(15) (16).

D2O and Hyperpolarized compounds

Deuterium oxide (D2O) has been used as an exogenous diffusible tracer for perfusion techniques before the clinical usage of gadolinium-based MRI contrast agents (17). Deuterium is a stable and nonradioactive isotope of hydrogen, and allows for the use of standard proton MR hardware and pulse sequences. However, the low sensitivity of direct deuterium detection (0.01 of that of 1H) has hindered its usage. Recently, two strategies have been proposed to enhance D2O perfusion contrast. The first indirect approach relies on the attenuation of 1H signal when the D2O molecules perfuse the tissue from the capillary bed. The feasibility of this approach has been shown on phantoms and in vivo rat brains (18). The second approach consists of dramatically increasing the sensitivity of direct D2O detection with hyperpolarization, i.e. using a dynamic nuclear polarization (dDNP) polarizer. This approach has been demonstrated for imaging of the renal arteries and kidney perfusion in a pig model (19)(20). In a similar way, metabolically inert 13C-labeled molecules can be used for angiographic and perfusion imaging in animal models (21)(22). Results obtained with hyperpolarized bis-1,1-(hydroxymethyl)-[1-13C]cyclopropane-d8 (HMCP) in tumor models have been shown to be strongly correlated with normalized peak height measured from DSC (gadolinium injection) images (23). The feasibility of human brain perfusion measurements using inhaled hyperpolarized xenon 129 (129Xe) has also been recently demonstrated (24).


No acknowledgement found.


1. Troprès I, Grimault S, Vaeth A, Grillon E, Julien C, Payen JF, et al. Vessel size imaging. Magn Reson Med Off J Soc Magn Reson Med Soc Magn Reson Med. 2001 Mar;45(3):397–408.

2. Dennie J, Mandeville JB, Boxerman JL, Packard SD, Rosen BR, Weisskoff RM. NMR imaging of changes in vascular morphology due to tumor angiogenesis. Magn Reson Med Off J Soc Magn Reson Med Soc Magn Reson Med. 1998 Dec;40(6):793–9.

3. Dósa E, Guillaume DJ, Haluska M, Lacy CA, Hamilton BE, Njus JM, et al. Magnetic resonance imaging of intracranial tumors: intra-patient comparison of gadoteridol and ferumoxytol. Neuro-Oncol. 2011 Feb;13(2):251–60.

4. Gahramanov S, Raslan AM, Muldoon LL, Hamilton BE, Rooney WD, Varallyay CG, et al. Potential for differentiation of pseudoprogression from true tumor progression with dynamic susceptibility-weighted contrast-enhanced magnetic resonance imaging using ferumoxytol vs. gadoteridol: a pilot study. Int J Radiat Oncol Biol Phys. 2011 Feb 1;79(2):514–23.

5. Christen T, Ni W, Qiu D, Schmiedeskamp H, Bammer R, Moseley M, et al. High-resolution cerebral blood volume imaging in humans using the blood pool contrast agent ferumoxytol. Magn Reson Med. 2013;70(3):705–710.

6. Christen T, Pannetier NA, Ni WW, Qiu D, Moseley ME, Schuff N, et al. MR vascular fingerprinting: A new approach to compute cerebral blood volume, mean vessel radius, and oxygenation maps in the human brain. NeuroImage. 2014 Apr 1;89:262–70.

7. Ogawa S, Lee TM, Kay AR, Tank DW. Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9868–72.

8. Germuska M, Bulte DP. MRI measurement of oxygen extraction fraction, mean vessel size and cerebral blood volume using serial hyperoxia and hypercapnia. NeuroImage. 2014 May 15;92:132–42.

9. Gauthier CJ, Hoge RD. Magnetic resonance imaging of resting OEF and CMRO₂ using a generalized calibration model for hypercapnia and hyperoxia. NeuroImage. 2012 Apr 2;60(2):1212–25.

10. Wise RG, Harris AD, Stone AJ, Murphy K. Measurement of OEF and absolute CMRO2: MRI-based methods using interleaved and combined hypercapnia and hyperoxia. NeuroImage. 2013 Dec;83:135–47.

11. Christen T, Jahanian H, Ni WW, Qiu D, Moseley ME, Zaharchuk G. Noncontrast mapping of arterial delay and functional connectivity using resting-state functional MRI: a study in Moyamoya patients. J Magn Reson Imaging JMRI. 2015 Feb;41(2):424–30.

12. Lv Y, Margulies DS, Cameron Craddock R, Long X, Winter B, Gierhake D, et al. Identifying the perfusion deficit in acute stroke with resting-state functional magnetic resonance imaging. Ann Neurol. 2013 Jan;73(1):136–40.

13. Amemiya S, Kunimatsu A, Saito N, Ohtomo K. Cerebral hemodynamic impairment: assessment with resting-state functional MR imaging. Radiology. 2014 Feb;270(2):548–55.

14. Lu H, Xu F, Grgac K, Liu P, Qin Q, van Zijl P. Calibration and validation of TRUST MRI for the estimation of cerebral blood oxygenation. Magn Reson Med Off J Soc Magn Reson Med Soc Magn Reson Med [Internet]. 2011 May 16 [cited 2011 Dec 7]; Available from:

15. Bolar DS, Rosen BR, Sorensen AG, Adalsteinsson E. QUantitative Imaging of eXtraction of oxygen and TIssue consumption (QUIXOTIC) using venular-targeted velocity-selective spin labeling. Magn Reson Med Off J Soc Magn Reson Med Soc Magn Reson Med. 2011 Dec;66(6):1550–62.

16. Hales PW, Kirkham FJ, Clark CA. A general model to calculate the spin-lattice (T1) relaxation time of blood, accounting for haematocrit, oxygen saturation and magnetic field strength. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2016 Feb;36(2):370–4.

17. Ackerman JJ, Ewy CS, Becker NN, Shalwitz RA. Deuterium nuclear magnetic resonance measurements of blood flow and tissue perfusion employing 2H2O as a freely diffusible tracer. Proc Natl Acad Sci U S A. 1987 Jun;84(12):4099–102.

18. Wang F-N, Peng S-L, Lu C-T, Peng H-H, Yeh T-C. Water signal attenuation by D2O infusion as a novel contrast mechanism for 1H perfusion MRI. NMR Biomed. 2013 Jun;26(6):692–8.

19. Lipsø KW, Hansen ESS, Tougaard RS, Laustsen C, Ardenkjaer-Larsen JH. Dynamic coronary MR angiography in a pig model with hyperpolarized water. Magn Reson Med. 2018 Jan 12;

20. Wigh Lipsø K, Hansen ESS, Tougaard RS, Laustsen C, Ardenkjaer-Larsen JH. Renal MR angiography and perfusion in the pig using hyperpolarized water. Magn Reson Med. 2017 Sep;78(3):1131–5.

21. Svensson J, Månsson S, Johansson E, Petersson JS, Olsson LE. Hyperpolarized 13C MR angiography using trueFISP. Magn Reson Med. 2003 Aug;50(2):256–62.

22. Johansson E, Månsson S, Wirestam R, Svensson J, Petersson JS, Golman K, et al. Cerebral perfusion assessment by bolus tracking using hyperpolarized 13C. Magn Reson Med. 2004 Mar;51(3):464–72.

23. Park I, von Morze C, Lupo JM, Ardenkjaer-Larsen JH, Kadambi A, Vigneron DB, et al. Investigating tumor perfusion by hyperpolarized13C MRI with comparison to conventional gadolinium contrast-enhanced MRI and pathology in orthotopic human GBM xenografts. Magn Reson Med. 2017 Feb;77(2):841–7.

24. Rao MR, Stewart NJ, Griffiths PD, Norquay G, Wild JM. Imaging Human Brain Perfusion with Inhaled Hyperpolarized129Xe MR Imaging. Radiology. 2018 Feb;286(2):659–65.

Proc. Intl. Soc. Mag. Reson. Med. 26 (2018)