Gadofosveset-based biomarker of tissue albumin concentration: Technical validation in vitro and feasibility in vivo

Abstract

Purpose: There is currently no adequate method of mapping physiologic and pathophysiologic tissue albumin concentrations in human subjects. The objective of this study was to devise and evaluate a biomarker of regional albumin concentration using gadofosveset-enhanced MRI.

Theory and methods: A binding and relaxation model was devised and evaluated in vitro in solutions of albumin at 3.0 Tesla (T) and 4.7T. The method was evaluated in the heart in seven volunteers at 3.0T.

Results: MRI-derived estimates of albumin concentration were in good agreement with true values over the range 0.1-1.0 mM (Pearson correlation coefficients of 0.85 and 0.88 for 3.0T and 4.7T, respectively). The mean calculated albumin concentration in the myocardium for the volunteers was 0.02 mM (range, 0.01-0.03 mM).

Conclusion: Accurate estimates of albumin concentration in vitro suggest this may be a viable noninvasive alternative to existing techniques. In the myocardium the MRI-derived estimates of albumin concentration indicate the practical feasibility of the technique but were below expected values. Gadofosveset-enhanced MR relaxometry has potential in providing biomarkers of regional albumin concentration; further evaluation is required before it can be used reliably in vivo.

Keywords: albumin; binding; biomarker; gadofosveset; relaxivity.

Figure 1

Modeled variation of ΔR₂ with gadofosveset concentration for three serum albumin concentrations, based on Eq. [14], assuming values of K_a = 11.0 mM⁻¹, r_2bound = 60.0 s⁻¹ mM⁻¹, r_2free = 6.1 s⁻¹ mM⁻¹ (29)

Figure 2

ΔR₁ (left column) and ΔR₂ (right column) values for gadofosveset at a range of albumin concentrations and for gadopentetate at 0.7 mM, at 3.0T (upper row) and 4.7T (lower row). Points represent measured values (with 95% confidence intervals); gadofosveset lines represent model fit based on relaxivities in Table 2; gadopentetate lines represent linear fit.

Figure 3

Bland–Altman plots of actual versus difference (calculated – actual) C_sa at 3.0T (26 plotted points) (a) and 4.7T (24 plotted points) (b). Dashed lines indicate standard deviation of difference

Figure 4

Calculated gadofosveset (a) and albumin (b) concentrations in myocardium (open symbols) and left ventricle (filled symbols) in healthy volunteers at 3.0T. Each symbol shape represents a different volunteer; values are plotted against time from first administration of contrast agent (to mid-point between T₁ and T₂ image acquisition times); error bars indicate uncertainty in calculations, calculated by propagation of errors using standard deviation of initial R₁ and R₂ ROI measurements (errors are symmetrical about data point, but only one side shown to aid clarity)