Diffusion tensor imaging of normal-appearing white matter as biomarker for radiation-induced late delayed cognitive decline.

PURPOSE: To determine whether early assessment of cerebral white matter degradation can predict late delayed cognitive decline after radiotherapy (RT). METHODS AND MATERIALS: Ten patients undergoing conformal fractionated brain RT participated in a prospective diffusion tensor magnetic resonance imaging study. Magnetic resonance imaging studies were acquired before RT, at 3 and 6 weeks during RT, and 10, 30, and 78 weeks after starting RT. The diffusivity variables in the parahippocampal cingulum bundle and temporal lobe white matter were computed. A quality-of-life survey and neurocognitive function tests were administered before and after RT at the magnetic resonance imaging follow-up visits. RESULTS: In both structures, longitudinal diffusivity (λ(‖)) decreased and perpendicular diffusivity (λ(⊥)) increased after RT, with early changes correlating to later changes (p < .05). The radiation dose correlated with an increase in cingulum λ(⊥) at 3 weeks, and patients with >50% of cingula volume receiving >12 Gy had a greater increase in λ(⊥) at 3 and 6 weeks (p < .05). The post-RT changes in verbal recall scores correlated linearly with the late changes in cingulum λ(‖) (30 weeks, p < .02). Using receiver operating characteristic curves, early cingulum λ(‖) changes predicted for post-RT changes in verbal recall scores (3 and 6 weeks, p < .05). The neurocognitive test scores correlated significantly with the quality-of-life survey results. CONCLUSIONS: The correlation between early diffusivity changes in the parahippocampal cingulum and the late decline in verbal recall suggests that diffusion tensor imaging might be useful as a biomarker for predicting late delayed cognitive decline.

Multiparametric magnetic resonance imaging and repeated measurements of blood-brain barrier permeability to contrast agents.

Breakdown of the blood-brain barrier (BBB) is present in several neurological disorders such as stroke, brain tumors, and multiple sclerosis. Noninvasive evaluation of BBB breakdown is important for monitoring disease progression and evaluating therapeutic efficacy in such disorders. One of the few techniques available for noninvasively and repeatedly localizing and quantifying BBB damage is magnetic resonance imaging (MRI). This usually involves the intravenous administration of a gadolinium-containing MR contrast agent (MRCA) such as Gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA), followed by dynamic contrast-enhanced MR imaging (DCE-MRI) of brain and blood, and analysis of the resultant data to derive indices of blood-to-brain transfer. There are two advantages to this approach. First, measurements can be made repeatedly in the same animal; for instance, they can be made before drug treatment and then again after treatment to assess efficacy. Secondly, MRI studies can be multiparametric. That is, MRI can be used to assess not only a blood-to-brain transfer or influx rate constant (Ki or K1) by DCE-MRI but also complementary parameters such as: (1) cerebral blood flow (CBF), done in our hands by arterial spin-tagging (AST) methods; (2) magnetization transfer (MT) parameters, most notably T1sat, which appear to reflect brain water-protein interactions plus BBB and tissue dysfunction; (3) the apparent diffusion coefficient of water (ADCw) and/or diffusion tensor, which is a function of the size and tortuosity of the extracellular space; and (4) the transverse relaxation time by T2-weighted imaging, which demarcates areas of tissue abnormality in many cases. The accuracy and reliability of two of these multiparametric MRI measures, CBF by AST and DCE-MRI determined influx of Gd-DTPA, have been established by nearly congruent quantitative autoradiographic (QAR) studies with appropriate radiotracers. In addition, some of their linkages to local pathology have been shown via corresponding light microscopy and fluorescence imaging. This chapter describes: (1) multiparametric MRI techniques with emphasis on DCE-MRI and AST-MRI; (2) the measurement of the blood-to-brain influx rate constant and CBF; and (3) the role of each in determining BBB permeability.

Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for prediction of radiation-induced neurocognitive dysfunction.

PURPOSE: To determine whether early assessment of cerebral microvessel injury can predict late neurocognitive dysfunction after brain radiation therapy (RT). EXPERIMENTAL DESIGN: Ten patients who underwent partial brain RT participated in a prospective dynamic contrast-enhanced magnetic resonance imaging (MRI) study. Dynamic contrast-enhanced MRI was acquired prior to, at weeks 3 and 6 during, and 1 and 6 months after RT. Neuropsychological tests were done pre-RT and at the post-RT MRI follow-ups. The correlations between early delayed changes in neurocognitive functions and early changes in vascular variables during RT were analyzed. RESULTS: No patients had tumor progression up to 6 months after RT. Vascular volumes and blood-brain barrier (BBB) permeability increased significantly in the high-dose regions during RT by 11% and 52% (P<0.05), respectively, followed by a decrease after RT. Changes in both vascular volume and BBB permeability correlated with the doses accumulated at the time of scans at weeks 3 and 6 during RT and 1 month after RT (P<0.03). Changes in verbal learning scores 6 months after RT were significantly correlated with changes in vascular volumes of left temporal (P<0.02) and frontal lobes (P<0.03), and changes in BBB permeability of left frontal lobes during RT (P<0.007). A similar correlation was found between recall scores and BBB permeability. CONCLUSION: Our data suggest that the early changes in cerebral vasculature may predict delayed alterations in verbal learning and total recall, which are important components of neurocognitive function. Additional studies are required for validation of these findings.

Radiation-induced changes in normal-appearing white matter in patients with cerebral tumors: a diffusion tensor imaging study.

PURPOSE: To quantify the radiation-induced changes in normal-appearing white matter before, during, and after radiotherapy (RT) in cerebral tumor patients. METHODS AND MATERIALS: Twenty-five patients with low-grade glioma, high-grade glioma, or benign tumor treated with RT were studied using diffusion tensor magnetic resonance imaging. The biologically corrected doses ranged from 50 to 81 Gy. The temporal changes were assessed before, during, and to 45 weeks after the start of RT. The mean diffusivity of water (), fractional anisotropy of diffusion, diffusivity perpendicular (lambdaperpendicular) and parallel (lambda||) to white matter fibers were calculated in normal-appearing genu and splenium of the corpus callosum. RESULTS: In the genu and splenium, fractional anisotropy decreased and , lambda||, lambdaperpendicular increased linearly and significantly with time (p<0.01). At 45 weeks after the start of RT, lambdaperpendicular had increased approximately 30% in the genu and splenium, and lambda|| had increased 5% in the genu and 9% in the splenium, suggesting that demyelination is predominant. The increases in lambdaperpendicular and lambda|| were dose dependent, starting at 3 weeks and continuing to 32 weeks from the start of RT. The dose-dependent increase in lambdaperpendicular and lambda|| was not sustained after 32 weeks, indicating the transition from focal to diffuse effects. CONCLUSION: The acute and subacute changes in normal-appearing white matter fibers indicate radiation-induced demyelination and mild structural degradation of axonal fibers. The structural changes after RT are progressive, with early dose-dependent demyelination and subsequent diffuse dose-independent demyelination and mild axonal degradation. Diffusion tensor magnetic resonance imaging is potentially a biomarker for the assessment of radiation-induced white matter injury.

Step-down infusions of Gd-DTPA yield greater contrast-enhanced magnetic resonance images of BBB damage in acute stroke than bolus injections.

A rat model of transient suture occlusion of one middle cerebral artery (MCA) was used to create a unilateral reperfused cerebral ischemic infarct with blood-brain barrier (BBB) opening. Opening of the BBB was visualized and quantitated by magnetic resonance (MR) contrast enhancement with a Look-Locker T(1)-weighted sequence either following an intravenous bolus injection (n=7) or during a step-down infusion (n=7) of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA). Blood levels of Gd-DTPA after either input were monitored via changes in sagittal sinus relaxation rate. Blood-to-brain influx constants (K(i)) were calculated by Patlak plots. On the basis of the MRI parameters and lesion size, the ischemic injury was determined to be similar in the two groups. The bolus injection input produced a sharp rise in blood levels of Gd-DTPA that declined quickly, whereas the step-down infusion led to a sharp rise that was maintained relatively constant for the period of imaging. Visual contrast enhancement and signal-to-noise (S/N) ratios were better with the step-down method (S/N=1.8) than with bolus injection (S/N=1.3). The K(i) values were not significantly different between the two groups (P>.05) and were around 0.005 ml/(g min). The major reason for the better imaging of BBB opening by the step-down infusion was the higher amounts of Gd-DTPA in plasma and tissue during most of the experimental period. These results suggest that step-down MR contrast agent (MRCA) administration schedule may be more advantageous for detection and delineation of acute BBB injury than the usually used bolus injections.

Quantitative characterization of hemodynamic properties and vasculature dysfunction of high-grade gliomas.

Aberrations in tumor and peritumoral vasculature may not be distinguishable by cerebral blood flow (CBF) or cerebral blood volume (CBV) alone. The relationships between CBF and CBV were examined to estimate vasculature-specific hemodynamic characteristics. Twenty glioma patients were studied with dynamic susceptibility T2*-weighted MRI [(dynamic contrast-enhanced magnetic resonance imaging (DSC-MRI)] before and during week 1 and 3 of radiotherapy (RT). CBF and CBV were calculated from DSC-MRI, and relationships between the two were evaluated: the physiological measure of mean transit time (MTT) = CBV/CBF; empirical fitting using the power law CBV = constant x (CBF)(beta). Three different tissue types were assessed: the Gd-enhancing tumor volume (GEV); non-enhanced abnormal tissue located beyond GEV but within the abnormal hyperintense region on FLAIR images (NEV); normal tissue in the hemisphere contralateral to the tumor (CNT). The effects of tissue types, CBV magnitudes (low, medium and high), before and during RT, on MTT and beta were analyzed by analysis of variance (ANOVA). The MTT and beta for the three tissue types were significantly different (p < 0.009). MTT increased from CNT (1.60 s) to NEV (1.93 s) to GEV (2.28 s) (p < 0.0005). beta was significantly greater in GEV (1.079) and NEV (1.070) than in CNT (1.025). Beta increased with increasing CBV magnitude while MTT was independent of CBV magnitude. There was a significant decrease in MTT of NEV and GEV during week 3 of RT compared with pre-RT values for all CBV magnitudes. There was a significant increase in beta during RT in the tumor and peritumor. Progressive abnormalities in vasculature and hemodynamic characteristics of the vascular bed were delineated, with significant disorder in the tumor but mild abnormality in peritumoral tissue.

The extent and severity of vascular leakage as evidence of tumor aggressiveness in high-grade gliomas.

Magnetic resonance imaging reveals heterogeneous regions within high-grade gliomas, such as a contrast-enhanced rim, a necrotic core, and non-contrast-enhanced abnormalities. It is unclear which of these regions best describes tumor aggressiveness. We hypothesized that the vascular leakage volume, reflecting disorganized angiogenesis typical of glioblastoma, would be a strong predictor of clinical outcome. The FLAIR tumor volume, post-gadolinium T1 tumor volume, tumor vascular leakage volume determined by dynamic contrast-enhanced imaging, and volume of the contrast-enhanced rim seen on post-gadolinium T1-weighted images were defined for 20 patients about to undergo treatment for newly diagnosed high-grade gliomas. The potential for imaging characteristics to improve prediction of survival and time to progression over clinical variables was tested by using Cox regression analysis. Single-variable Cox regression analysis of each of the four tumor subvolumes revealed that the vascular leakage volume was the only significant predictor of survival. When the joint effect of clinical variables and the vascular leakage volume were tested for prediction of survival, only the age and the vascular leakage volume were selected as significant predictors. However, when time to progression was tested as a dependent variable, both the vascular leakage volume and the vascular permeability were selected as copredictors, along with surgical status. Our findings suggest that for patients with high-grade glioma, time to progression after radiation therapy is influenced by both underlying biological aggressiveness (vascularity) and volume of aggressive tumor. In contrast, survival depends chiefly on the volume of aggressive tumor at the time of presentation.

Survival prediction in high-grade gliomas by MRI perfusion before and during early stage of RT [corrected].

PURPOSE: To determine whether cerebral blood volume (CBV) and cerebral blood flow can predict the response of high-grade gliomas to radiotherapy (RT) by taking into account spatial heterogeneity and temporal changes in perfusion. METHODS AND MATERIALS: Twenty-three patients with high-grade gliomas underwent conformal RT, with magnetic resonance imaging perfusion before and at Weeks 1-2 and 3-4 during RT. Tumor perfusion was classified as high, medium, or low. The prognostic values of pre-RT perfusion and the changes during RT for early prediction of tumor response to RT were evaluated. RESULTS: The fractional high-CBV tumor volume before RT and the fluid-attenuated inversion recovery imaging tumor volume were identified as predictors for survival (p = 0.01). Changes in tumor CBV during the early treatment course also predicted for survival. Better survival was predicted by a decrease in the fractional low-CBV tumor volume at Week 1 of RT vs. before RT, a decrease in the fractional high-CBV tumor volume at Week 3 vs. Week 1 of RT, and a smaller pre-RT fluid-attenuated inversion recovery imaging tumor volume (p = 0.01). CONCLUSION: Early temporal changes during RT in heterogeneous regions of high and low perfusion in gliomas might predict for different physiologic responses to RT. This might also open the opportunity to identify tumor subvolumes that are radioresistant and might benefit from intensified RT.

Quantitation and localization of blood-to-brain influx by magnetic resonance imaging and quantitative autoradiography in a model of transient focal ischemia.

The ability of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) enhanced MRI to localize and quantitate blood-brain barrier (BBB) opening was evaluated against quantitative autoradiographic (QAR) imaging of (14)C-alpha-aminoisobutyric acid (AIB) distribution. The blood-to-brain transfer constant (K(i)) for Gd-DTPA was determined by MRI in rats after 3 h of focal cerebral ischemia plus 2.5 h of reperfusion (n = 9), and that of AIB was determined by QAR shortly thereafter. Tissue regions of interest (ROIs) for Gd-DTPA leakage were identified by ISODATA segmentation of pre- and post-Gd-DTPA Look-Locker (L-L) T(1) maps. Patlak plots were constructed using time course of blood and tissue T(1) changes induced by Gd for estimating K(i). Among the nine rats, 14 sizable regions of AIB uptake were found; 13 were also identified by ISODATA segmentation. Although the 13 MRI-ROIs spatially approximated those of AIB uptake, the segmentation sometimes missed small areas of lesser AIB uptake that did not extend through more than 60% of the 2.0-mm-thick slice. Mean K(i)'s of AIB were highly correlated with those of Gd-DTPA across the 13 regions; the group means (+/-SD) were similar for the two tracers (7.1 +/- 3.3 x 10(-3) and 6.8 +/- 3.5 x 10(-3) ml.g(-1) . min(-1), respectively). In most instances, Gd-DTPA MRI accurately localized areas of BBB opening.

Acute blood-brain barrier opening in experimentally induced focal cerebral ischemia is preferentially identified by quantitative magnetization transfer imaging.

Pathologic changes in brain tissue during and after stroke may lead to injury of the blood-brain barrier (BBB) and subsequent hemorrhagic transformation (HT). In a rat model of HT, the apparent diffusion coefficient of water, cerebral blood flow, relaxation times, T(1) and T(2), and magnetization transfer (MT) related parameters (T(1sat), K(for) and the MT ratio) were repetitively measured during 3 h of focal ischemia and 2 h of reperfusion (n = 8). Areas of BBB opening were identified by sequential assay of the transcapillary influx of Gd-diethylenetriaminepentaacetic acid (Gd-DTPA) by MRI and (14)C-alpha-aminoisobutyric acid (AIB) by quantitative autoradiography. Ischemia-injured regions of interest were identified from the MRI data and divided into those with and without BBB opening. Of the several MRI parameters measured, the T(1sat) in the caudate-putamen and preoptic area during ischemia and the first 2 h of reperfusion correlated best with the regional pattern of BBB opening observed thereafter. These data suggest that an ipsilateral/contralateral T(1sat) ratio > 1.6 demarcates leakage of small molecules such as Gd-DTPA and AIB across the BBB. As to clinical relevance, the quantitation of MT parameters in acute stroke may enable the early detection of areas of BBB opening and potential HT.

Early prediction of gross hemorrhagic transformation by noncontrast agent MRI cluster analysis after embolic stroke in rat.

BACKGROUND AND PURPOSE: Our goal was to develop magnetic resonance indices, without image contrast agent enhancement, that predict hemorrhagic transformation (HT) in a rat model of embolic stroke. METHODS: Male Wistar rats subjected to embolic stroke with (n=12) or without (n=10) the combination treatment with recombinant tissue plasminogen activator and an anti-platelet glycoprotein IIb/IIIa antibody 7E3 F(ab')2 initiated at 4 hours after onset of stroke were investigated using a 7-T MRI system. Radiofrequency saturation T1 (T1sat) maps with magnetization transfer, apparent diffusion coefficient of water (ADCw) maps in 3 directions, and T2 maps were measured at 2, 24, and 48 hours after embolization. MRI data were analyzed individually and using 2D cluster plots. Histological measurements were obtained at 48 hours. RESULTS: Gross hemorrhage was detected at 48 hours in 7 (4 control, 3 treated) of 22 animals. The 2D cluster plot using MRI T1sat and ADCw maps obtained at 2 hours after stroke predicted all gross HT. The location of gross hemorrhage predicted by the 2D cluster plot was within 0.75 mm of the identifying MRI cluster. CONCLUSIONS: The 2D MRI cluster plot analysis using T1sat and ADCw maps acquired at 2 hours after the onset of embolic stroke predicts gross HT.

Patlak plots of Gd-DTPA MRI data yield blood-brain transfer constants concordant with those of 14C-sucrose in areas of blood-brain opening.

The blood-to-brain transfer rate constant (K(i)) of Gd-DTPA was determined in MRI studies of a rat model of transient cerebral ischemia. The longitudinal relaxation rate, R(1), was estimated using repeated Look-Locker measurements. A model-independent analysis of deltaR(1), the Patlak plot, produced maps of K(i) for Gd-DTPA and the distribution volume of the mobile protons (V(p)) with intravascular-Gd changed R(1)'s. The K(i)'s of Gd-DTPA were estimated in regions of interest with blood-brain barrier (BBB) opening (regions of interest, ROIs) and compared to those of (14)C-sucrose determined shortly thereafter by quantitative autoradiography. The K(i)'s for both Gd-DTPA and sucrose were much higher than normal within the ROIs (n = 7); linear regression of K(i) for Gd-DTPA vs. K(i) for sucrose yielded a slope of 0.43 +/- 0.11 and r(2) = 0.72 (P = 0.01). Thus, K(i) for Gd-DTPA varied in parallel with, but was less than, K(i) for sucrose. In the ROIs, mean V(p) was 0.071 ml g(-1) and much higher than mean vascular volume estimated by dynamic-contrast-enhancement (0.013 ml g(-1)) or mean V(p) in contralateral brain (0.015 ml g(-1)). This elevated V(p) may reflect increased capillary permeability to water. In conclusion, K(i) can be reliably calculated from Gd-DTPA-MRI data by Patlak plots.