David L. Buckley

Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer: standardized quantities and symbols

We describe a standard set of quantity names and symbols related to the estimation of kinetic parameters from dynamic contrast‐enhanced T1‐weighted magnetic resonance imaging data, using diffusable agents such as gadopentetate dimeglumine (Gd‐DTPA). These include a) the volume transfer constant Ktrans (min−1); b) the volume of extravascular extracellular space (EES) per unit volume of tissue ve (0 < ve < 1); and c) the flux rate constant between EES and plasma kep (min−1). The rate constant is the ratio of the transfer constant to the EES (kep = Ktrans/ve). Under flow‐limited conditions Ktrans equals the blood plasma flow per unit volume of tissue; under permeability‐limited conditions Ktrans equals the permeability surface area product per unit volume of tissue. We relate these quantities to previously published work from our groups; our future publications will refer to these standardized terms, and we propose that these be adopted as international standards. J. Magn. Reson. Imaging 10:223–232, 1999.

Experimentally-derived functional form for a population-averaged high-temporal-resolution arterial input function for dynamic contrast-enhanced MRI

Rapid T1‐weighted 3D spoiled gradient‐echo (GRE) data sets were acquired in the abdomen of 23 cancer patients during a total of 113 separate visits to allow dynamic contrast‐enhanced MRI (DCE‐MRI) analysis of tumor microvasculature. The arterial input function (AIF) was measured in each patient at each visit using an automated AIF extraction method following a standardized bolus administration of gadodiamide. The AIFs for each patient were combined to obtain a mean AIF that is representative for any individual. The functional form of this general AIF may be useful for studies in which AIF measurements are not possible. Improvements in the reproducibility of DCE‐MRI model parameters (Ktrans, ve, and vp) were observed when this new, high‐temporal‐resolution population AIF was used, indicating the potential for increased sensitivity to therapy‐induced change. Magn Reson Med, 2006.

Uncertainty in the analysis of tracer kinetics using dynamic contrast-enhanced T1-weighted MRI

In recent years a number of physiological models have gained prominence in the analysis of dynamic contrast‐enhanced T1‐weighted MRI data. However, there remains little evidence to support their use in estimating the absolute values of tissue physiological parameters such as perfusion, capillary permeability, and blood volume. In an attempt to address this issue, data were simulated using a distributed pathway model of tracer kinetics, and three published models were fitted to the resultant concentration‐time curves. Parameter estimates obtained from these fits were compared with the parameters used for the simulations. The results indicate that the use of commonly accepted models leads to systematic overestimation of the transfer constant, Ktrans, and potentially large underestimates of the blood plasma volume fraction, Vp. In summary, proposals for a practical approach to physiological modeling using MRI data are outlined. Magn Reson Med 47:601–606, 2002.

Tracer kinetic modelling in MRI: estimating perfusion and capillary permeability

The tracer-kinetic models developed in the early 1990s for dynamic contrast-enhanced MRI (DCE-MRI) have since become a standard in numerous applications. At the same time, the development of MRI hardware has led to increases in image quality and temporal resolution that reveal the limitations of the early models. This in turn has stimulated an interest in the development and application of a second generation of modelling approaches. They are designed to overcome these limitations and produce additional and more accurate information on tissue status. In particular, models of the second generation enable separate estimates of perfusion and capillary permeability rather than a single parameter K(trans) that represents a combination of the two. A variety of such models has been proposed in the literature, and development in the field has been constrained by a lack of transparency regarding terminology, notations and physiological assumptions. In this review, we provide an overview of these models in a manner that is both physically intuitive and mathematically rigourous. All are derived from common first principles, using concepts and notations from general tracer-kinetic theory. Explicit links to their historical origins are included to allow for a transfer of experience obtained in other fields (PET, SPECT, CT). A classification is presented that reveals the links between all models, and with the models of the first generation. Detailed formulae for all solutions are provided to facilitate implementation. Our aim is to encourage the application of these tools to DCE-MRI by offering researchers a clearer understanding of their assumptions and requirements.

On the scope and interpretation of the Tofts models for DCE-MRI.

The Tofts model (TM) and extended Tofts model (ETM) have become a standard for the analysis of dynamic contrast‐enhanced MRI. In this study, a mathematical analysis is used to identify exactly in which tissue types the Tofts models may be applied. The results show that the TM is accurate if and only if the tissue is weakly vascularised (small blood volume). The ETM is additionally accurate in highly perfused tissues (high blood flow). In tissues that are highly vascularised, or where tracer exchange is very fast or very slow, TM and ETM accurately fit the data but lead to a misinterpretation of the parameters. In tissue types with intermediate vascularity, perfusion and tracer exchange, neither model offers a good fit to the tissue concentrations. A good fit can be obtained with a measured input function by reducing the temporal resolution, but this does not improve the accuracy of the parameters. In conclusion, the Tofts models only produce reliable parameter values if the tissue is weakly vascularized (TM or ETM) or highly perfused (ETM). Without prior knowledge that at least one of these constraints is fulfilled, the physiological interpretation of the values produced by the Tofts models is unclear. Magn Reson Med, 2011.

Classic models for dynamic contrast‐enhanced MRI

Dynamic contrast‐enhanced MRI (DCE‐MRI) is a functional MRI method where T1 ‐weighted MR images are acquired dynamically after bolus injection of a contrast agent.

Prediction of radiotherapy outcome using dynamic contrast enhanced MRI of carcinoma of the cervix

PURPOSE To investigate whether analysis of MRI enhancement data using a pharmacokinetic model improved a previously found correlation between contrast enhancement and tumor oxygenation measured using PO2 histograph. To evaluate the prognostic value of gadolinium enhancement data for radiotherapy outcome, and to study the efficacy of combined enhancement and MRI volume data. METHODS AND MATERIALS Fifty patients underwent dynamic gadolinium-enhanced MRI as part of their initial staging investigations before treatment. Gadolinium enhancement was analyzed using the Brix pharmacokinetic model to obtain the parameters amplitude and rate of contrast enhancement. Pretreatment tumor oxygen measurements (Eppendorf PO2 histograph) were available for 35 patients. RESULTS Both standard and pharmacokinetic-derived enhancement data correlated with tumor oxygenation measurements, and poorly enhancing tumors had low tumor oxygen levels. However, only the pharmacokinetic-analyzed data correlated with patient outcome and patients with poorly (amplitude less than median) vs. well-enhancing tumors had significantly worse disease-specific survival (p = 0.024). For the 50 patients studied, no relationship was found between enhancement and volume data. Combining MRI volume and enhancement information highlighted large differences in outcome (p = 0.0054). At the time of analysis, only 55% of patients with large, poorly enhanced tumors were alive compared with 92% of patients with small, well-enhanced tumors. CONCLUSION These preliminary results suggest that pharmacokinetic modeling of dynamic contrast-enhanced MRI provides data that reflect tumor oxygenation and yields useful prognostic information in patients with locally advanced carcinoma of the cervix. Combining MRI-derived enhancement and volume data delineates large differences in radiotherapy outcome.

Quantitative imaging biomarkers in the clinical development of targeted therapeutics: current and future perspectives.

Targeted therapeutics have challenged how imaging techniques assess tumour response to treatment because many new agents are thought to cause cytostasis rather than cytotoxicity. Advanced tracer development, image acquisition, and image analysis have been used to produce quantitative biomarkers of pathophysiology, with particular focus on measurement of tumour vascular characteristics. Here, we critically appraise strategies available to generate imaging biomarkers for use in development of targeted therapeutics. We consider important practical and technical features of data acquisition and analysis because these factors determine the precise physiological meaning of every biomarker. We discuss the merits of volume-based and other size-based metrics for assessment of targeted therapeutics, and we examine the strengths and weaknesses of CT, MRI, and PET biomarkers derived from conventional clinical data. We review imaging biomarkers of tumour microvasculature and discuss imaging strategies that probe other physiological processes including cell proliferation, apoptosis, and tumour invasion. We conclude on the need to develop comprehensive compound-specific imaging biomarkers that are appropriate for every class of targeted therapeutics, and to investigate the complementary information given in multimodality imaging studies of targeted therapeutics.

Visualization of neural tissue water compartments using biexponential diffusion tensor MRI

The apparent diffusion tensor (ADT) imaging method was extended to account for multiple diffusion components. A biexponential ADT imaging experiment was used to obtain separate images of rapidly and slowly diffusing water fractions in excised rat spinal cord. The fast and slow component tensors were compared and found to exhibit similar gross features, such as fractional anisotropy, in both white and gray matter. However, there were also some important differences, which are consistent with the different structures occupying intracellular and extracellular spaces. Evidence supporting the assignment of the two tensor components to extracellular and intracellular water fractions is provided by an NMR spectroscopic investigation of homogeneous samples of brain tissue. Magn Reson Med 45:580–587, 2001.

Magnetic resonance imaging screening in women at genetic risk of breast cancer: imaging and analysis protocol for the UK multicentre study

The imaging and analysis protocol of the UK multicentre study of magnetic resonance imaging (MRI) as a method of screening for breast cancer in women at genetic risk is described. The study will compare the sensitivity and specificity of contrast-enhanced MRI with two-view x-ray mammography. Approximately 500 women below the age of 50 at high genetic risk of breast cancer will be recruited per year for three years, with annual MRI and x-ray mammography continuing for up to 5 years. A symptomatic cohort will be measured in the first year to ensure consistent reporting between centres. The MRI examination comprises a high-sensitivity three-dimensional contrast-enhanced assessment, followed by a high-specificity contrast-enhanced study in equivocal cases. Multiparametric analysis will encompass morphological assessment, the kinetics of contrast agent uptake and determination of quantitative pharmacokinetic parameters. Retrospective analysis will identify the most specific indicators of malignancy. Sensitivity and specificity, together with diagnostic performance, diagnostic impact and therapeutic impact will be assessed with reference to pathology, follow-up and changes in diagnostic certainty and therapeutic decisions. Mammography, lesion localisation, pathology and cytology will be performed in accordance with the UK NHS Breast Screening Programme quality assurance standards. Similar standards of quality assurance will be applied for MR measurements and evaluation.