Kathleen M. Schmainda

Characterization of continuously distributed cortical water diffusion rates with a stretched-exponential model

Experience with diffusion‐weighted imaging (DWI) shows that signal attenuation is consistent with a multicompartmental theory of water diffusion in the brain. The source of this so‐called nonexponential behavior is a topic of debate, because the cerebral cortex contains considerable microscopic heterogeneity and is therefore difficult to model. To account for this heterogeneity and understand its implications for current models of diffusion, a stretched‐exponential function was developed to describe diffusion‐related signal decay as a continuous distribution of sources decaying at different rates, with no assumptions made about the number of participating sources. DWI experiments were performed using a spin‐echo diffusion‐weighted pulse sequence with b‐values of 500–6500 s/mm2 in six rats. Signal attenuation curves were fit to a stretched‐exponential function, and 20% of the voxels were better fit to the stretched‐exponential model than to a biexponential model, even though the latter model had one more adjustable parameter. Based on the calculated intravoxel heterogeneity measure, the cerebral cortex contains considerable heterogeneity in diffusion. The use of a distributed diffusion coefficient (DDC) is suggested to measure mean intravoxel diffusion rates in the presence of such heterogeneity. Magn Reson Med 50:727–734, 2003.

Comparison of Dynamic Susceptibility-weighted Contrast-enhanced MR Methods: Recommendations for Measuring Relative Cerebral Blood Volume in Brain Tumors

PURPOSE To investigate whether estimates of relative cerebral blood volume (rCBV) in brain tumors, obtained by using dynamic susceptibility-weighted contrast material-enhanced magnetic resonance (MR) imaging vary with choice of data acquisition and postprocessing methods. MATERIALS AND METHODS Four acquisition methods were used to collect data in 22 high-grade glioma patients, with informed written consent under HIPAA-compliant guidelines approved by the institutional review board. During bolus administration of a standard single dose of gadolinium-based contrast agent (0.1 mmol per kilogram of body weight), one of three acquisition methods was used: gradient-echo (GRE) echo-planar imaging (echo time [TE], 30 msec; flip angle, 90 degrees ; n = 10), small-flip-angle GRE echo-planar imaging (TE, 54 msec; flip angle, 35 degrees ; n = 7), or dual-echo GRE spiral-out imaging (TE, 3.3 and 30 msec; flip angle, 72 degrees ; n = 5). Next, GRE echo-planar imaging (TE, 30 msec; flip angle, 90 degrees ; n = 22) was used to collect data during administration of a second dose of contrast agent (0.2 mmol/kg). Subsequently, six methods of analysis were used to calculate rCBV. Mean rCBV values from whole tumor, tumor hot spots, and contralateral brain were normalized to mean rCBV in normal-appearing white matter. RESULTS Friedman two-way analysis of variance and Kruskal-Wallis one-way analysis of variance results indicated that qualitative rCBV values were dependent on acquisition and postprocessing methods for both tumor and contralateral brain. By using the nonparametric Mann-Whitney test, a consistently positive (greater than zero) tumor-contralateral brain rCBV ratio resulted when either the preload-postprocessing correction approach or dual-echo acquisition approach (P < .008 for both methods) was used. CONCLUSION The dependence of tumor rCBV on the choice of acquisition and postprocessing methods is caused by their varying sensitivities to T1 and T2 and/or T2* leakage effects. The preload-correction approach and dual-echo acquisition approach are the most robust choices for the evaluation of brain tumors when the possibility of contrast agent extravasation exists.

Validation of functional diffusion maps (fDMs) as a biomarker for human glioma cellularity

To present comprehensive examinations of the assumptions made in functional diffusion map (fDM) analyses and provide a biological basis for fDM classification.

Lesion-induced pseudo-dominance at functional magnetic resonance imaging: implications for preoperative assessments

OBJECTIVE:To illustrate how lesion-induced neurovascular uncoupling at functional magnetic resonance imaging (fMRI) can mimic hemispheric dominance opposite the side of a lesion preoperatively. METHODS:We retrospectively reviewed preoperative fMRI mapping data from 50 patients with focal brain abnormalities to establish patterns of hemispheric dominance of language, speech, visual, or motor system functions. Abnormalities included gliomas (31 patients), arteriovenous malformations (AVMs) (11 patients), other congenital lesions (4 patients), encephalomalacia (3 patients), and tumefactive encephalitis (1 patient). A laterality ratio of fMRI hemispheric dominance was compared with actual hemispheric dominance as verified by electrocortical stimulation, Wada testing, postoperative and posttreatment deficits, and/or lesion-induced deficits. fMRI activation maps were generated with cross-correlation (P < 0.001) or t test (P < 0.001) analysis. RESULTS:In 50 patients, a total of 85 functional areas were within 5 mm of the edge of a potentially resectable lesion. In 23 of these areas (27%), reduced fMRI signal in perilesional eloquent cortex in conjunction with preserved or increased signal in homologous contralateral brain areas revealed functional dominance opposite the side of the lesion. This suggested possible lesion-induced transhemispheric cortical reorganization to homologous brain regions (homotopic reorganization). In seven patients, however, the fMRI data were inconsistent with other methods of functional localization. In two patients with left inferior frontal gyrus gliomas and in one patient with focal tumefactive meningoencephalitis, fMRI incorrectly suggested strong right hemispheric speech dominance. In two patients with lateral precentral gyrus region gliomas and one patient with a left central sulcus AVM, the fMRI pattern incorrectly suggested primary corticobulbar motor dominance contralateral to the side of the lesion. In a patient with a right superior frontal gyrus AVM, fMRI revealed pronounced left dominant supplementary motor area activity in response to a bilateral complex motor task, but right superior frontal gyrus perilesional hemorrhage and edema subsequently caused left upper-extremity plegia. Pathophysiological factors that might have caused neurovascular uncoupling and facilitated pseudo-dominance at fMRI in these patients included direct tumor infiltration, neovascularity, cerebrovascular inflammation, and AVM-induced hemodynamic effects. Sixteen patients had proven (1 patient), probable (2 patients), or possible (13 patients) but unproven lesion-induced homotopic cortical reorganization. CONCLUSION:Lesion-induced neurovascular uncoupling causing reduced fMRI signal in perilesional eloquent cortex, in conjunction with normal or increased activity in homologous brain regions, may simulate hemispheric dominance and lesion-induced homotopic cortical reorganization.

MR-derived cerebral blood volume maps: Issues regarding histological validation and assessment of tumor angiogenesis

In an effort to develop MRI methods for the evaluation of tumor angiogenesis (new blood vessel formation), MRI‐derived cerebral blood volume (CBV) information has been compared to histologic measures of microvessel density (MVD). Although MVD is a standard marker of angiogenesis, it is not a direct correlate of the volume measurements made with MRI, and therefore inappropriate for the development and validation of the MR techniques. Therefore, the goal of this study was to develop an approach by which MR measurements of CBV can be directly correlated. To this end, dynamic susceptibility contrast (DSC) MRI experiments were performed in six Fisher rats implanted with 9L gliosarcoma brain tumors. Subsequently, the circulation was perfused with a latex compound (Microfil®), after which 50‐μm tissue sections were analyzed for vessel count, diameter, and the fraction of area comprised of vessels. The results demonstrate that while fractional area (FA) does not provide a good measure of CBV, FA corrected for section thickness effects does. Whereas the FA in normal brain was found to be 13.03 ± 1.83% the corrected FA, or fractional volume (FV), was 1.89 ± 0.39%, a value in agreement with those reported in the literature for normal brain. Furthermore, while no significant difference was found between normal brain and tumor FA (P = 0.55), the difference was significant for FV (P = 0.036), as would be expected. And only with FV does a correlation with the MRI‐derived CBV become apparent (rS = 0.74). There was strong correlation (rs = 0.886) between the tumor / normal blood volume ratios as estimated by each technique, although the MR‐ratio (1.56 ± 0.29) underestimated the histologic‐ratio (2.35 ± 0.75). Thus, the correlation of MRI CBV methods requires a measurement of fractional vessel area and correction of this area for section thickness effects. This new independent correlative measure should enable efficient and accurate progress in the development of MRI methods to evaluate tumor angiogenesis. Magn Reson Med 46:735–747, 2001.

Dynamic-susceptibility contrast agent MRI measures of relative cerebral blood volume predict response to bevacizumab in recurrent high-grade glioma

BACKGROUND The anti-VEGF antibody, bevacizumab, is standard treatment for patients with recurrent glioblastoma. In this setting, traditional anatomic MRI methods such as post-contrast T1-weighted and T2-weighted imaging are proving unreliable for monitoring response. Here we evaluate the prognostic significance of pre- and posttreatment relative cerebral blood volume (rCBV) derived from dynamic susceptibility contrast MRI to predict response to bevacizumab. METHODS Thirty-six participants with recurrent high-grade gliomas who underwent rCBV imaging 60 days before and 20-60 days after starting bevacizumab treatment were enrolled. Tumor regions of interest (ROIs) were determined from deltaT1 maps computed from the difference between standardized post and precontrast T1-weighted images. Both pre- and posttreatment rCBV maps were corrected for leakage and standardized (stdRCBV) to a consistent intensity scale. The Kaplan-Meier method was used to determine if either the pre- or post-bevacizumab stdRCBV within the tumor ROI was predictive of overall survival (OS) or progression free survival (PFS). RESULTS The OS was significantly longer if either the pre- (380d vs 175d; P=.0024) or posttreatment stdRCBV (340d vs 186d; P = .0065) was <4400. The posttreatment stdRCBV was also predictive of PFS (167d vs 78d; P = .0006). When the stdRCBV values were both above versus both below threshold, the OS was significantly worse (100.5d vs 395d; P < .0001). With a 32.5% decrease in stdRCBV, the risk of death was reduced by about 68% but increased by 140% with a 29% increase in stdRCBV. CONCLUSIONS Standardized rCBV is predictive of OS and PFS in patients with recurrent high-grade brain tumor treated with bevacizumab.

Water exchange and inflow affect the accuracy of T1‐GRE blood volume measurements: Implications for the evaluation of tumor angiogenesis

The goal of this study was to determine the degree to which vascular water exchange and blood flowing into an imaging slice affect the accuracy of blood volume measurements of brain and tumor tissue when using intravascular T1 contrast agents. The study was performed using 2D and 3D gradient‐echo imaging sequences, since these are two of the most commonly used MRI methods used to evaluate tissue blood volume fraction. Computer simulations were performed and measurements made in a rat 9L gliosarcoma brain tumor model. The computer simulations demonstrate that, with either water exchange or inflow effects alone, the dependence on the physiologic and imaging parameters can be well characterized and therefore potentially offset. In the exchange only case, the parametric dependence of 3D simulations suggest that the best accuracy is achieved with high flip angles, short TR, and low blood contrast agent concentrations. However, for a 2D GRE sequence which is influenced by both water exchange and inflow, the simulations predict that the error trend as a function of the imaging and physiologic parameters is unpredictable and therefore difficult to compensate. With both 2D and 3D GRE the measured blood volume data in rat brain and tumor tissue demonstrate tissue‐specific trends, which reflect differences in the considered physiologic parameters. The experimental data strongly support the computer simulations and also indicate that minimization of the physiological effects by proper selection of imaging parameters, contrast concentration, and volume calculation methods is crucial for accurate assessment of absolute blood volume fraction. Magn Reson Med 47:1110–1120, 2002.

A novel technique for modeling susceptibility-based contrast mechanisms for arbitrary microvascular geometries: The finite perturber method

Recently, we demonstrated that vessel geometry is a significant determinant of susceptibility-induced contrast in MRI. This is especially relevant for susceptibility-contrast enhanced MRI of tumors with their characteristically abnormal vessel morphology. In order to better understand the biophysics of this contrast mechanism, it is of interest to model how various factors, including microvessel morphology contribute to the measured MR signal, and was the primary motivation for developing a novel computer modeling approach called the Finite Perturber Method (FPM). The FPM circumvents the limitations of traditional fixed-geometry approaches, and enables us to study susceptibility-induced contrast arising from arbitrary microvascular morphologies in 3D, such as those typically observed with brain tumor angiogenesis. Here we describe this new modeling methodology and some of its applications. The excellent agreement of the FPM with theory and the extant susceptibility modeling data, coupled with its computational efficiency demonstrates its potential to transform our understanding of the factors that engender susceptibility contrast in MRI.

The Role of Preload and Leakage Correction in Gadolinium-Based Cerebral Blood Volume Estimation Determined by Comparison with MION as a Criterion Standard

BACKGROUND AND PURPOSE: Contrast extravasation in DSC-MRI potentiates inaccurate and imprecise estimates of glioma rCBV. We tested assertions that preload and postprocessing algorithms minimize this error by comparing Gd-rCBV using permutations of these 2 techniques with criterion standard rCBV using MION, an intravascular agent. MATERIALS AND METHODS: We imaged 7 Fisher rats with 9L gliosarcomas, by using 3T gradient-echo DSC-MRI with MION (2.0 mg Fe/kg) and staged injection of Gd-diethylene triamine pentaacetic acid: a 0.1-mmol/kg bolus provided no preload (P−) data and served as preload (P+) for a subsequent 0.2-mmol/kg bolus. We computed MION-rCBV (steady-state ΔR2*, tumor versus normal brain) and Gd-rCBV ΔR2* [t] integration) without (C−) and with (C+) postprocessing correction, thereby testing 4 correction permutations: P−C−, P−C+, P+C−, and P+C+. We tested whether each permutation reduced bias and variance of the Gd/MION rCBV differences by using generalized estimating equations and Fmax statistics (P < .05 significant). RESULTS: Gd-rCBV progressively better approximated MION-rCBV with increasing leakage correction. There was no statistically significant bias for the mean percentage deviation of Gd-rCBV from MION-rCBV for any correction permutation, but there was significantly reduced variance by using P+C− (22-fold), P−C+ (32-fold), and P+C+ (267-fold) compared with P−C−. P+C+ provided significant additional variance reduction compared with P+C− (12-fold) and P−C+ (8-fold). Linear regression of Gd-rCBV versus MION-rCBV revealed P+C+ to have the closest slope and intercept compared with the ideal, substantially better than P+C−. CONCLUSIONS: Preload and postprocessing correction significantly reduced the variance of Gd-rCBV estimates, and bias reduction approached significance. Postprocessing correction provide significant benefit beyond preload alone.

Volumetric analysis of functional diffusion maps is a predictive imaging biomarker for cytotoxic and anti-angiogenic treatments in malignant gliomas

Anti-angiogenic agents targeting brain tumor neovasculature may increase progression-free survival in patients with recurrent malignant gliomas. However, when these patients do recur it is not always apparent as an increase in enhancing tumor volume on MRI, which has been the standard of practice for following patients with brain tumors. Therefore alternative methods are needed to evaluate patients treated with these novel therapies. Furthermore, a method that can also provide useful information for the evaluation of conventional therapies would provide an important advantage for general applicability. Diffusion-weighted magnetic resonance imaging (DWI) has the potential to serve as a valuable biomarker for these purposes. In the current study, we explore the prognostic ability of functional diffusion maps (fDMs), which examine voxel-wise changes in the apparent diffusion coefficient (ADC) over time, applied to regions of fluid-attenuated inversion recovery (FLAIR) abnormalities in patients with malignant glioma, treated with either anti-angiogenic or cytotoxic therapies. Results indicate that the rate of change in fDMs is an early predictor of tumor progression, time to progression and overall survival for both treatments, suggesting the application of fDMs in FLAIR abnormal regions may be a significant advance in brain tumor biomarker technology.