Paul S. Tofts

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.

Normal cerebral perfusion measurements using arterial spin labeling: reproducibility, stability, and age and gender effects.

Before meaningful conclusions can be drawn from clinical measures of cerebral blood perfusion, the precision of the measurement must be determined and set in the context of inter‐ and intrasubject sources of variability. This work establishes the reproducibility of perfusion measurements using the noninvasive MRI technique of continuous arterial spin labeling (CASL). Perfusion was measured in 34 healthy normal subjects. Intersubject variability was assessed, and age and gender contributions were estimated. Intersubject variation was found to be large, with up to 100% perfusion difference for subjects of the same age and gender. Repeated measurements in one subject showed that perfusion remains remarkably stable in the short term when compared with intersubject variation and the large capacity for perfusion change in the brain. A significant decrease in the ratio of gray‐matter to white‐matter perfusion was found with increasing age (0.79% per year (P < 0.0005)). This appears to be due mainly to a reduction in gray‐matter perfusion, which was found to decrease by 0.45% per year (P = 0.04). Regional analysis suggested that the gray‐matter age‐related changes were predominantly localized in the frontal cortex. Whole‐brain perfusion was 13% higher (P = 0.02) in females compared to males. Magn Reson Med 51:736–743, 2004.

MR imaging of tumor microcirculation: Promise for the new millenium†

Dynamic contrast‐enhanced magnetic resonance imaging (DCE MRI) is a method of imaging the physiology of the microcirculation. A series of recent clinical studies have shown that DCE MRI can measure and predict tumor response to therapy. Recent advances in MR technology provide the enhanced spatial and temporal resolution that allow the application of this methodology in the management of cancer patients. The September issue of this journal provided a microcirculation section to update readers on this exciting and challenging topic. Evidence is mounting that DCE MRI‐based measures correlate well with tumor angiogenesis. DCE MRI has already been shown in several types of tumors to correlate well with traditional outcome measures, such as histopathologic studies, and with survival. These new measures are sensitive to tumor physiology and to the pharmacokinetics of the contrast agent in individual tumors. Moreover, they can present anatomical images of tumor microcirculation at excellent spatial resolution. Several issues have emerged from recent international workshops that must be addressed to move this methodology into routine clinical practice. First, is complex modeling of DCE MRI really necessary to answer clinical questions reliably? Clinical research has shown that, for tumors such as bone sarcomas, reliable outcome measures of tumor response to chemotherapy can be extracted from DCE MRI by methods ranging from simple measures of enhancement to pharmacokinetic models. However, the use of similar methods to answer a different question—the differentiation of malignant from benign breast tumors—has yielded contradictory results. Thus, no simple, one‐size‐fits‐all‐tumors solution has yet been identified. Second, what is the most rational and reliable data collection procedure for the DCE MRI evaluation? Several groups have addressed population variations in some key variables, such as tumor T10 (T1 prior to contrast administration) and the arterial input function Ca(t) for contrast agent, and how they influence the precision and accuracy of DCE MRI outcomes. However, despite these potential complications, clinical studies in this section show that some tumor types can be assessed by relatively simple dynamic measures and analyses. The clinical scenario and tumor type may well determine the required complexity of the DCE MRI exam procedure and its analysis. Finally, we suggest that a consensus on naming conventions (nomenclature) is needed to facilitate comparison and analysis of the results of studies conducted at different centers. J. Magn. Reson. Imaging 10:903–907, 1999.

High field MRI correlates of myelin content and axonal density in multiple sclerosis--a post-mortem study of the spinal cord.

Abstract.Different MRI techniques are used to investigate multiple sclerosis (MS) in vivo. The pathological specificity of these techniques is poorly understood, in particular their relationship to demyelination and axonal loss.The aim of this study was to evaluate the pathological substrate of high field MRI in post-mortem (PM) spinal cord (SC) of patients with MS. MRI was performed in PMSCs of four MS patients and a healthy subject on a 7 Tesla machine.Quantitative MRI maps (PD; T2; T1; magnetization transfer ratio, MTR; diffusion weighted imaging) were obtained. After scanning, the myelin content and the axonal density of the specimens were evaluated neuropathologically using quantitative techniques. Myelin content and axonal density correlated strongly with MTR, T1, PD, and diffusion anisotropy, but only moderately with T2 and weakly with the apparent diffusion coefficient.Quantitative MR measures provide a promising tool to evaluate components of MS pathology that are clinically meaningful. Further studies are warranted to investigate the potential of new quantitative MR measures to enable a distinction between axonal loss and demyelination and between demyelinated and remyelinated lesions.

Quantitative magnetic resonance of postmortem multiple sclerosis brain before and after fixation

Unfixed and fixed postmortem multiple sclerosis (MS) brain is being used to probe pathology underlying quantitative MR (qMR) changes. Effects of fixation on qMR indices in MS brain are unknown. In 15 postmortem MS brain slices T1, T2, MT ratio (MTR), macromolecular proton fraction (fB), fractional anisotropy (FA), and mean, axial, and radial diffusivity (MD, Dax, and Drad) were assessed in white matter (WM) lesions (WML) and normal appearing WM (NAWM) before and after fixation in formalin. Myelin content, axonal count, and gliosis were quantified histologically. Students t‐test and regression were used for analysis. T1, T2, MTR, and fB obtained in unfixed MS brain were similar to published values obtained in patients with MS in vivo. Following fixation T1, T2 (NAWM, WML) and MTR (NAWM) dropped, whereas fB (NAWM, WML) increased. Compared to published in vivo data all diffusivity measures were lower in unfixed MS brain, and dropped further following fixation (except for FA). MTR was the best predictor of Tmyelin (inversely related to myelin) in unfixed MS brain (r = −0.83; P < 0.01) whereas postfixation T2 (r = 0.92; P < 0.01), T1 (r = 0.89; P < 0.01), and fB (r = −0.86; P < 0.01) were superior. All diffusivity measures (except for Dax in unfixed tissue) were predictors of myelin content. Magn Reson Med 59:268–277, 2008.

Heterogeneity of blood‐brain barrier changes in multiple sclerosis An MRI study with gadolinium‐DTPA enhancement

We performed 15 dynamic gadolinium-DTPA (Gd-DTPA)-enhanced MRI studies in 8 patients with relapsing and remitting multiple sclerosis; 7 were follow-up studies. We measured the time course of enhancement in 102 enhancing lesions for up to 384 minutes, with rest breaks. Immediate postcontrast MRIs demonstrated many different patterns of enhancement. We observed both uniformly enhancing and ring enhancing lesions. The enhancing regions were often less extensive than the corresponding high signal on T2-weighted images. Three lesions were seen with Gd-DTPA but not on unenhanced scans; 1 was seen on unenhanced scans 10 days later, suggesting that blood-brain barrier disturbance may precede other MRI signs of MS lesions. Three months later, some high-signal areas on T2-weighted scans had decreased in size to resemble the areas previously outlined by Gd-DTPA. This technique provides useful information about the pathogenesis and behavior of MS lesions.

Quantitative Magnetization Transfer Imaging in Postmortem Multiple Sclerosis Brain

To investigate the relationship of myelin content, axonal density, and gliosis with the fraction of macromolecular protons (fB) and T2 relaxation of the macromolecular pool (T2B) acquired using quantitative magnetization transfer (qMT) MRI in postmortem brains of subjects with multiple sclerosis (MS).

Test liquids for quantitative MRI measurements of self-diffusion coefficient in vivo

A range of liquids suitable as quality control test objects for measuring the accuracy of clinical MRI diffusion sequences (both apparent diffusion coefficient and tensor) has been identified and characterized. The self‐diffusion coefficients for 15 liquids (3 cyclic alkanes: cyclohexane to cyclooctane, 9 n‐alkanes: n‐octane to n‐hexadecane, and 3 n‐alcohols: ethanol to 1‐propanol) were measured at 15–30°C using an NMR spectrometer. Values at 22°C range from 0.36 to 2.2 10−9 m2s−1. Typical 95% confidence limits are ±2%. Temperature coefficients are 1.7–3.2 %/°C. T1 and T2 values at 1.5 T and proton density are given. n‐tridecane has a diffusion coefficient close to that of normal white matter. The longer n‐alkanes may be useful T2 standards. Measurements from a spin‐echo MRI sequence agreed to within 2%. Magn Reson Med 43:368–374, 2000.

Improved accuracy of human cerebral blood perfusion measurements using arterial spin labeling: accounting for capillary water permeability

A two‐compartment exchange model for perfusion quantification using arterial spin labeling (ASL) is presented, which corrects for the assumption that the capillary wall has infinite permeability to water. The model incorporates an extravascular and a blood compartment with the permeability surface area product (PS) of the capillary wall characterizing the passage of water between the compartments. The new model predicts that labeled spins spend longer in the blood compartment before exchange. This makes an accurate blood T1 measurement crucial for perfusion quantification; conversely, the tissue T1 measurement is less important and may be unecessary for pulsed ASL experiments. The model gives up to 62% reduction in perfusion estimate for human imaging at 1.5T compared to the single compartment model. For typical human perfusion rates at 1.5T it can be assumed that the venous outflow signal is negligible. This simplifies the solution, introducing only one more parameter than the single compartment model, PS/vbw, where vbw is the fractional blood water volume per unit volume of tissue. The simplified model produces an improved fit to continuous ASL data collected at varying delay time. The fitting yields reasonable values for perfusion and PS/vbw. Magn Reson Med 48:27–41, 2002.

Correction of intensity nonuniformity in MR images of any orientation

The specialised radiofrequency (RF) coils used in MRI such as head or surface coils can give rise to marked image intensity nonuniformities. There are two situations in which it is essential to correct this: (1) When a global intensity threshold is used to segment particular tissues; and (2) in proton density images, from which the proton concentration can be measured provided that the system gain is uniform or known over the whole image. We describe experiments to determine the magnitude and sources of nonuniformity in a 0.5-T system, and assess methods devised to correct for them in scans of any orientation, including oblique scans at arbitrary angles to the magnet axis and arbitrary offsets from the magnet iso-centre. A correction based on the response of a system to a uniform phantom was implemented. Tests of the correction with orthogonal views demonstrate that the uniformity of images of any orientation can be improved significantly with a correction matrix from just one orientation and still further with two matrices, one axial and the other either coronal or sagittal. We expect further improvements to be possible if gradient coil eddy current effects can be reduced.