Synopsis

DCE-MRI experiments are designed to measure tracer exchange. We can choose to make them sensitive to water exchange but in doing so we compromise their ability to measure tracer exchange, particularly their ability to measure the arterial input function (AIF). The choice is simple, EITHER measure tracer exchange parameters alone and well OR measure tracer exchange and water exchange parameters together but poorly.

Target Audience & Educational Objectives

• Clinicians, biomedical engineers and basic scientists who are interested in DCE-MRI of the brain and body with a focus on perfusion, capillary permeability and metabolism.

Upon completion of this lecture, participants should be able to:

• Understand the basic difference between the water-exchange and tracer-exchange paradigm;
• Understand the conceptual arguments underpinning opposing views; and
• Demonstrate a good overview of the experimental evidence supporting either side of the argument.

1. Water exchange (WX) and dynamic contrast-enhanced (DCE) MRI

• We perform DCE imaging experiments and analyse the time course to make estimates of hemodynamic parameters such as blood flow (F), blood volume (v_b), capillary permeability surface-area product (PS) and interstitial volume (v_e) [1].
• With dynamic radiotracer imaging experiments (PET, SPECT) or DCE-CT we image the tracer directly and there’s a straightforward relationship between signal and tracer concentration. With DCE-MRI the relationship is more complicated because we don’t measure the tracer (gadolinium based contrast agent, GBCA) directly but rather measure its effect on water in its local environment.
• If that water is moving freely through the tissue (fast exchange) then WX can be neglected, we simply measure a single average tissue R1 (1/T1), subtract the baseline R1(0) (1/T1(0)) and the difference is directly proportional to tissue tracer concentration. If the water moves more slowly between tissue compartments (e.g. between interstitium and cell) and the difference between the R1s of those compartments increases (such as when GBCA enters the interstitium but not the cell) then we might begin to see multiple T1s in that tissue and then can’t perform our simple subtraction.
• Since a DCE-MRI experiment is expected to observe GBCA in the interstitium we perhaps, in principle, might see the effect of WX in our DCE signal-time course. The question is, how much of an effect does WX have on our DCE-MRI experiment?

2. Historical perspective

• Measurements of WX have been made using MR for a long time [2].
• Like DCE-MRI many of these experiments employed contrast agents (typically Mn-based) to reduce the T1 or T2 of water in one compartment. Unlike DCE-MRI, they typically employed high doses of contrast agent and made measurements during a steady-state rather than in a dynamic phase.
• Experiments of this type continue to be performed and can provide important information about WX [3]. For example, relatively recent experiments on yeast cells [4] employed steady-state GBCA at a concentration of 9.3 mM, levels only seen in DCE-MRI experiments in the arterial blood plasma at the peak of the GBCA bolus (i.e. for a few seconds).
• Hence it can be seen that while there’s a historical precedent for contrast-enhanced measures of WX, those experiments took a very different form.

3. Recent approaches to measuring WX using DCE-MRI

• More recently the influence of WX on CE-MRI has been examined in some detail (e.g. [5-10]).
• While it’s broadly agreed that WX between capillary and interstitium (transendothelial) can have a significant effect upon CE measurements, the picture with cell-interstitial (transcytolemmal) exchange is less clear.
• The Springer lab developed a modeling approach to estimating DCE parameters and WX parameters simultaneously – the shutter-speed model [7,11]. The so-called fast exchange regime allowed (FXR-a) version of this approach has been used by numerous groups to analyze their DCE-MRI data (e.g. [12-14]).
• The FXR-a version makes an unnecessary simplifying assumption about the relationship between signal intensity and GBCA concentration that can lead to inaccurate estimates of the model parameters as the WX rate slows down [9].
• Moreover, it’s apparent that many of the estimates of WX-related parameters made in these studies (e.g. τ_i, intracellular residence time of water), are imprecise [9,10].
• Nevertheless, this model has generated great interest in the DCE-MRI community not least because it usually fits the data better than the standard Tofts model [15] and it produces an additional parameter estimate, τ_i.

4.Necessary conditions for quantitative DCE-MRI

• The issue of precision was addressed in the historical WX measurements. In order to obtain sufficient sensitivity to WX a large dose of contrast agent was used. Clinical DCE-MRI doesn’t use a lot of GBCA. Furthermore, DCE-MRI sequences are, by necessity, exchange-minimized; optimized to reduce sensitivity to WX [16]. In order to measure signal intensity changes in both tissue and a feeding artery (the arterial input function, AIF) where the signal changes are both rapid and avid, the pulse sequence uses short TR and relatively high flip angles [17].
• The need to measure an AIF is a key problem with all quantitative DCE-MRI experiments. If the AIF isn’t measured well then all subsequent parameter estimation is compromised since it plays a central role in dictating the shape and scale of the tissue signal time course [1, 18].
• While a recent study that suggests τ_i is insensitive to AIF scaling [19], AIF scaling (partial volume) isn’t the main problem as it can be corrected. When measuring the AIF issues such as temporal sampling, inflow effects, pulse sequence sensitivity, B1 and so on, have much more detrimental effects on the AIF [20,21].
• If the AIF is measured properly then we can select the optimal model to describe our DCE-MRI data [22] and when studying tumors, the optimal model is unlikely to be a Tofts model because this doesn’t sufficiently describe the enhancement seen in vascular tissues [23].
• To date, DCE-MRI studies attempting to estimate WX in which measurement of the AIF was a key consideration either were unable to observe a measureable effect of WX [24,25] or used a Tofts model that failed to describe the early vascular contribution to the signal time course in the tumors studied [12,13]. The improvement in the fit obtained by the addition of the WX parameter could be seen as confirmation of a significant WX perturbation or as a partial correction for an inappropriate choice of tracer kinetic model. The latter hypothesis is supported by the simulation study of Zhang & Kim where an appropriate choice of tracer kinetic model left no need for WX terms [10]. They concluded that more work is needed before τ_i is used for practical application.

5. Summary

• The measurement of WX is an important issue worthy of exploration by the MR community and may provide useful information about tissues in vivo. However, there is considerably more work required before it can be measured reliably by DCE-MRI methods alone; it is clear that quantitative DCE-MRI experiments are simply not sensitive enough.

Acknowledgements

References

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