Thomas L. Chenevert

DIAGNOSIS OF PULMONARY EMBOLISM WITH MAGNETIC RESONANCE ANGIOGRAPHY

BACKGROUND Diagnosing pulmonary embolism may be difficult, because there is no reliable noninvasive imaging method. We compared a new noninvasive method, gadolinium-enhanced pulmonary magnetic resonance angiography, with standard pulmonary angiography for diagnosing pulmonary embolism. METHODS A total of 30 consecutive patients with suspected pulmonary embolism underwent both standard pulmonary angiography and magnetic resonance angiography during the pulmonary arterial phase at the time of an intravenous bolus of gadolinium. All magnetic resonance images were reviewed for the presence or absence of pulmonary emboli by three independent reviewers who were unaware of the findings on standard angiograms. RESULTS Pulmonary embolism was detected by standard pulmonary angiography in 8 of the 30 patients in whom pulmonary embolism was suspected. All 5 lobar emboli and 16 of 17 segmental emboli identified on standard angiograms were also identified on magnetic resonance images. Two of the three reviewers reported one false positive magnetic resonance angiogram each. As compared with standard pulmonary angiography, the three sets of readings had sensitivities of 100, 87, and 75 percent and specificities of 95, 100, and 95 percent, respectively. The interobserver correlation was good (k=0.57 to 0.83 for all vessels, 0.49 to 1.0 for main and lobar vessels, and 0.40 to 0.81 for segmental vessels). CONCLUSIONS In this preliminary study, gadolinium-enhanced magnetic resonance angiography of the pulmonary arteries, as compared with conventional pulmonary angiography, had high sensitivity and specificity for the diagnosis of pulmonary embolism. This new technique shows promise as a noninvasive method of diagnosing pulmonary embolism without the need for ionizing radiation or iodinated contrast material.

Noninvasive real-time imaging of apoptosis

Strict coordination of proliferation and programmed cell death (apoptosis) is essential for normal physiology. An imbalance in these two opposing processes results in various diseases including AIDS, neurodegenerative disorders, myelodysplastic syndromes, ischemia/reperfusion injury, cancer, autoimmune disease, among others. Objective and quantitative noninvasive imaging of apoptosis would be a significant advance for rapid and dynamic screening as well as validation of experimental therapeutic agents. Here, we report the development of a recombinant luciferase reporter molecule that when expressed in mammalian cells has attenuated levels of reporter activity. In cells undergoing apoptosis, a caspase-3-specific cleavage of the recombinant product occurs, resulting in the restoration of luciferase activity that can be detected in living animals with bioluminescence imaging. The ability to image apoptosis noninvasively and dynamically over time provides an opportunity for high-throughput screening of proapoptotic and antiapoptotic compounds and for target validation in vivo in both cell lines and transgenic animals.

Gadolinium-Enhanced Magnetic Resonance Angiography for Pulmonary Embolism: A Multicenter Prospective Study (PIOPED III)

BACKGROUND The accuracy of gadolinium-enhanced magnetic resonance pulmonary angiography and magnetic resonance venography for diagnosing pulmonary embolism has not been determined conclusively. OBJECTIVE To investigate performance characteristics of magnetic resonance angiography, with or without magnetic resonance venography, for diagnosing pulmonary embolism. DESIGN Prospective, multicenter study from 10 April 2006 to 30 September 2008. SETTING 7 hospitals and their emergency services. PATIENTS 371 adults with diagnosed or excluded pulmonary embolism. MEASUREMENTS Sensitivity, specificity, and likelihood ratios were measured by comparing independently read magnetic resonance imaging with the reference standard for diagnosing pulmonary embolism. Reference standard diagnosis or exclusion was made by using various tests, including computed tomographic angiography and venography, ventilation-perfusion lung scan, venous ultrasonography, d-dimer assay, and clinical assessment. RESULTS Magnetic resonance angiography, averaged across centers, was technically inadequate in 25% of patients (92 of 371). The proportion of technically inadequate images ranged from 11% to 52% at various centers. Including patients with technically inadequate images, magnetic resonance angiography identified 57% (59 of 104) with pulmonary embolism. Technically adequate magnetic resonance angiography had a sensitivity of 78% and a specificity of 99%. Technically adequate magnetic resonance angiography and venography had a sensitivity of 92% and a specificity of 96%, but 52% of patients (194 of 370) had technically inadequate results. LIMITATION A high proportion of patients with suspected embolism was not eligible or declined to participate. CONCLUSION Magnetic resonance pulmonary angiography should be considered only at centers that routinely perform it well and only for patients for whom standard tests are contraindicated. Magnetic resonance pulmonary angiography and magnetic resonance venography combined have a higher sensitivity than magnetic resonance pulmonary angiography alone in patients with technically adequate images, but it is more difficult to obtain technically adequate images with the 2 procedures.

Functional diffusion map as an early imaging biomarker for high-grade glioma: correlation with conventional radiologic response and overall survival.

PURPOSE Assessment of radiologic response (RR) for brain tumors utilizes the Macdonald criteria 8 to 10 weeks from the start of treatment. Diffusion magnetic resonance imaging (MRI) using a functional diffusion map (fDM) may provide an earlier measure to predict patient survival. PATIENTS AND METHODS Sixty patients with high-grade glioma were enrolled onto a study of intratreatment MRI at 1, 3, and 10 weeks. Receiver operating characteristic curve analysis was used to evaluate imaging parameters as a function of patient survival at 1 year. Both log-rank and Cox proportional hazards models were utilized to assess overall survival. RESULTS Greater increases in diffusion in response to therapy over time were observed in those patients alive at 1 year compared with those who died as a result of disease. The volume of tumor with increased diffusion by fDM at 3 weeks was the strongest predictor of patient survival at 1 year, with larger fDM predicting longer median survival (52.6 v 10.9 months; log-rank, P < .003; hazard ratio [HR] = 2.7; 95% CI, 1.5 to 5.9). Radiologic response at 10 weeks had similar prognostic value (median survival, 31.6 v 10.9 months; log-rank P < .0007; HR = 2.9; 95% CI, 1.7 to 7.2). Radiologic response and fDM differed in 25% of cases. A composite index of response including fDM and RR provided a robust predictor of patient survival and may identify patients in whom RR does not correlate with clinical outcome. CONCLUSION Compared with conventional neuroimaging, fDM provided an earlier assessment of equal predictive value, and the combination of fDM and RR provided a more accurate prediction of patient survival than either metric alone.

Order Information in Working Memory: fMRI Evidence for Parietal and Prefrontal Mechanisms

Working memory is thought to include a mechanism that allows for the coding of order information. One question of interest is how order information is coded, and how that code is neurally implemented. Here we report both behavioral and fMRI findings from an experiment that involved comparing two tasks, an item-memory task and an order-memory task. In each case, five letters were presented for storage, followed after a brief interval by a set of probe letters. In the case of the item-memory task, the two letters were identical, and the subject responded to the question, Was this letter one of the items you saw?. In the case of the order-memory task, the letters were different, and subjects responded to the question, Are these two letters in the order in which you saw them?. Behaviorally, items that were further apart in the sequence elicited faster reaction times and higher accuracy in the Order task. Areas that were significantly more activated in the Order condition included the parietal and prefrontal cortex. Parietal activations overlapped those involved in number processing, leading to the suggestion that the underlying representation of order and numbers may share a common process, coding for magnitude.

The parametric response map is an imaging biomarker for early cancer treatment outcome

Here we describe the parametric response map (PRM), a voxel-wise approach for image analysis and quantification of hemodynamic alterations during treatment for 44 patients with high-grade glioma. Relative cerebral blood volume (rCBV) and flow (rCBF) maps were acquired before treatment and after 1 and 3 weeks of therapy. We compared the standard approach using region-of-interest analysis for change in rCBV or rCBF to the change in perfusion parameters on the basis of PRM (PRMrCBV and PRMrCBF) for their accuracy in predicting overall survival. Neither the percentage change of rCBV or rCBF predicted survival, whereas the regional response evaluations made on the basis of PRM were highly predictive of survival. Even when accounting for baseline rCBV, which is prognostic, PRMrCBV proved more predictive of overall survival.

Clinical applications of diffusion tensor imaging.

Directionally‐ordered cellular structures that impede water motion, such as cell membranes and myelin, result in water mobility that is also directionally‐dependent. Diffusion tensor imaging characterizes this directional nature of water motion and thereby provides structural information that cannot be obtained by standard anatomic imaging. Quantitative apparent diffusion coefficients and fractional anisotropy have emerged from being primarily research tools to methods enabling valuable clinical applications. This review describes the clinical utility of diffusion tensor imaging, including the basic principles of the technique, acquisition, data analysis, and the major clinical applications. J. Magn. Reson. Imaging 2004;19:6–18.

Parametric Response Map As an Imaging Biomarker to Distinguish Progression From Pseudoprogression in High-Grade Glioma

PURPOSE To assess whether a new method of quantifying therapy-associated hemodynamic alterations may help to distinguish pseudoprogression from true progression in patients with high-grade glioma. PATIENTS AND METHODS Patients with high-grade glioma received concurrent chemoradiotherapy. Relative cerebral blood volume (rCBV) and blood flow (rCBF) maps were acquired before chemoradiotherapy and at week 3 during treatment on a prospective institutional review board-approved study. Pseudoprogression was defined as imaging changes 1 to 3 months after chemoradiotherapy that mimic tumor progression but stabilized or improved without change in treatment or for which resection revealed radiation effects only. Clinical and conventional magnetic resonance (MR) parameters, including average percent change of rCBV and CBF, were evaluated as potential predictors of pseudoprogression. Parametric response map (PRM), an innovative, voxel-by-voxel method of image analysis, was also performed. RESULTS Median radiation dose was 72 Gy (range, 60 to 78 Gy). Of 27 patients, stable disease/partial response was noted in 13 patients and apparent progression was noted in 14 patients. Adjuvant temozolomide was continued in all patients. Pseudoprogression occurred in six patients. Based on PRM analysis, a significantly reduced blood volume (PRM(rCBV)) at week 3 was noted in patients with progressive disease as compared with those with pseudoprogression (P < .01). In contrast, change in average percent rCBV or rCBF, MR tumor volume changes, age, extent of resection, and Radiation Therapy Oncology Group recursive partitioning analysis classification did not distinguish progression from pseudoprogression. CONCLUSION PRM(rCBV) at week 3 during chemoradiotherapy is a potential early imaging biomarker of response that may be helpful in distinguishing pseudoprogression from true progression in patients with high-grade glioma.

A Novel Polyacrylamide Magnetic Nanoparticle Contrast Agent for Molecular Imaging using MRI

A novel polyacrylamide superparamagnetic iron oxide nanoparticle platform is described which has been synthetically prepared such that multiple crystals of iron oxide are encapsulated within a single polyacrylamide matrix (PolyAcrylamide Magnetic [PAM] nanoparticles). This formulation provides for an extremely large T2 and T2* relaxivity of between 620 and 1140 sec(-1) mM(-1). Administration of PAM nanoparticles into rats bearing orthotopic 9L gliomas allowed quantitative pharmacokinetic analysis of the uptake of nanoparticles in the vasculature, brain, and glioma. Addition of polyethylene glycol of varying sizes (0.6, 2, and 10 kDa) to the surface of the PAM nanoparticles resulted in an increase in plasma half-life and affected tumor uptake and retention of the nanoparticles as quantified by changes in tissue contrast using MRI. The flexible formulation of these nanoparticles suggests that future modifications could be accomplished allowing for their use as a targeted molecular imaging contrast agent and/or therapeutic platform for multiple indications.

Motion Correction in fMRI via Registration of Individual Slices Into an Anatomical Volume

An automated retrospective image registration based on mutual information is adapted to a multislice functional magnetic resonance imaging (fMRI) acquisition protocol to provide accurate motion correction. Motion correction is performed by mapping each slice to an anatomic volume data set acquired in the same fMRI session to accommodate inter‐slice head motion. Accuracy of the registration parameters was assessed by registration of simulated MR data of the known truth. The widely used rigid body volume registration approach based on stacked slices from the time series data may hinder statistical accuracy by introducing inaccurate assumptions of no motion between slices for multislice fMRI data. Improved sensitivity and specificity of the fMRI signal from mapping‐each‐slice‐to‐volume method is demonstrated in comparison with a stacked‐slice correction method by examining functional data from two normal volunteers. The data presented in a standard anatomical coordinate system suggest the reliability of the mapping‐each‐slice‐to‐volume method to detect the activation signals consistent between the two subjects. Magn Reson Med 41:964–972, 1999.