Outline Project Proposal
Investigation into the Usage of Oxygen-Enhanced MRI outside the Lungs
Project Aims:
 To implement methods for measuring oxygen-enhanced MRI (OE-MRI) in
tissues and organs outside the lung
 To extend these methods to quantitative parametric mapping of dynamic OEMRI in the imaged locations
 To use the findings to suggest usage of this technique in the diagnosis of
relevant conditions and diseases
Hypotheses:
 Naish et al [1] showed that the effective concentration of oxygen in lung
parenchyma can be determined and monitored using OE MRI as it changes
between breathing 100% O2 and air. We hypothesise that similar
measurements can be made for other organs and tissues.
 Time courses of tissues can be modelled to provide quantitative, reproducible
information about the flow and diffusion of O2 through various organs and
tissues.
 These measurements will provide unique functional information in diseases
such as cancer.
Background:
Oxygen-Enhanced MRI has been shown to provide information on regional delivery
of oxygen within the lung. The method relies on parenchymal blood T1 reduction in
the presence of high concentrations of oxygen in the lung air-spaces to produce signal
intensity changes. Initial examination of the images obtained during the OE-MRI lung
study by Naish et al has shown a response in various tissues to the presence of
dissolved oxygen, in particular in muscle and the spleen. As a preliminary
investigation, similar wash-in and wash-out curves to those for the lungs have been
plotted. Uptake time maps of the body trunk have also been generated which illustrate
a range of uptake times in various tissues and organs surrounding the lungs. OE-MRI
would therefore appear to have a wide range of applicability, while holding the
advantages over other means of examination of being non-invasive, non-ionising and
relatively high-resolution. Another advantage of the technique is that it requires little
specialist equipment or scanning procedures and is therefore relatively inexpensive
and easily implemented.
Previous Literature:
Functional imaging based on the change in T1 induced by inhaling pure oxygen was
first used by Young et al [2]to study signal changes in the left ventricle of the heart.
Edelman et al later demonstrated oxygen enhanced imaging in the lung. Tadamura et
al [3] used the same technique to study various tissues, including the myocardium,
liver, spleen, skeletal muscle, subcutaneous fat, bone marrow, and arterial blood.
They observed a statistically significant decrease of T1 relaxation times in the
myocardium, spleen and arterial blood, whereas no significant change was observed
in liver, subcutaneous fat, bone marrow or (contrary to our initial findings) skeletal
muscle. Noseworthy et al [4] examined blood and muscle T1 and T2 relaxivity under
normoxic and hyperoxic conditions. They found a decrease in T1 for arterial blood
and an increase in T2 for venous blood, but again no change in T1 for muscle.
However using a bi-exponential model for T2 they noted an increase in a component
of the T2 model for muscle. As regards T1 measurements in muscle it is worthwhile
noting that Tadamura et al used the dorsal skeletal muscles and Noseworthy et al the
calf muscles for their measurements. These muscles receive blood flow at a later time
than the shoulder muscles we have examined (?), and are likely to benefit less from
increased oxygenation. More recently Jones et al [5]have demonstrated T1 shortening
in the kidneys and spleen. Much work has been carried out on measuring the effects
of breathing carbogen on tumour oxygenation, e.g. Griffiths et al [6]. Measurements
of the characteristics of response of various tissues and organs to pure O2 could be
used in turn for similar examinations of pathologies.
Draft Work Plan:
Acquisition protocols for T1-weighted and T2*-weighted O2 imaging will be
implemented. Oxygen breathing equipment will be constructed (same equipment as
planned for O2 lung project) and tested. Acquisition protocols will be optimised for
dynamic OE-MRI and volunteer scans acquired. O2 time courses on wash-in and
wash-out will be modelled in a range of target organs to define normal tissue uptake
characteristics. 10 volunteers will be scanned in total.
No patients will be studied in this work. However, depending on which organs exhibit
useful functional information, it is possible that follow-on disease studies would be
possible (in, for example, tumours, pancreas, spleen, liver, muscle).
Number of PDF months required
6
Non-Staff Costs
Scanning costs (including breathing equipment) ~ £7000.
Proposed Start and End Dates
start: Feb 2005, end: July/August 2005
Milestones
 Construction of breathing equipment (in parallel with O2 lung project)
 Replication of published static enhancement studies
 Development of dynamic OE-MRI protocol
 Characterisation of normal tissue O2 uptake/washout
 Identification of possible disease areas for further study
Outputs
1: Information sought by AZ
 Are these techniques likely to be sensitive to pathology?
 Are these techniques able to characterise normal tissue function consistently
across a group?

Can a clinical application be of possible use to provide markers in therapeutic
trials of experimental agents?
2: Publication Opportunities
 Methods publication
 Clinical publication if applied in patients
Strategic Fit AZ
Novel non-invasive biomarkers that provide information related to tissue function are
of potential application in trials of a range of compounds. For example, an index of
oxygen diffusion within tumours would provide a surrogate for growth potential. This
project is relatively ‘blue sky’ as it involves the implementation and evaluation of
techniques that are currently unfamiliar to us, but which could provide unique in vivo
information.
Strategic Fit University
Interest in dynamic contrast enhanced MRI in general and also methods to measure
tumour oxygenation (GP). Complementary work to on-going lung oxygenation
project.
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6.
Naish JH, P.G., Beatty PC, Jackson A, Waterton JC, Young SS and Taylor CJ,
"Improved regional analysis of oxygen-enhanced lung MR imaging using
image registration". Lect Notes Comp Sci, 2004. 3216: p. p 862-869.
Young IR, C.G., Bailes DR, Pennock JM, Doyle FH and Bydder GM,
Enhancement of Relaxation Rate with Paramagnetic Contrast Agents in NMR
Imaging. Jounal of Computer Assisted Tomography, 1981. 5: p. 543-547.
Tadamura E, H.H., Li W, Prasad P, Edelman R, Effect of Oxygen Inhalation
on Relaxation Times in Various Tissues. Journal of Magnetic Resonance
Imaging, 1997. 7(1).
Noseworthy MD, K.J., Stainsby JA, Stanisz GJ and Wright GA, Tracking
Oxygen Effects on MR Signal in Blood and Skeletal Muscle During Hyperoxia
Exposure. Journal of Magnetic Resonance Imaging, 1999. 9: p. 814-820.
Jones RA, R.M., Moonen CTW and Grenier N, Imaging the Changes in Renal
T1 Induced by the Inhalation of Pure Oxygen: A Feasibility Study. Magnetic
Resonance in Medicine, 2002. 47: p. 728-735.
Griffiths JR, T.N., Howe FA, Saunders MI,Robinson S,Hoskin PJ, Powell
MEB,Thoumine M, Caine LA, and Baddeley H, The Response of Human
Tumours to Carbogen Breathing, Monitored by Gradient-Recalled Echo
Magnetic Resonance Imaging. International Journal of Radiation Oncology
Biology Physics, 1997. 39(3): p. 697-701.