Vijaya Nagesh

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.

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.

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.

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.

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 14C‐α‐aminoisobutyric acid (AIB) distribution. The blood‐to‐brain transfer constant (Ki) 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) T1 maps. Patlak plots were constructed using time course of blood and tissue T1 changes induced by Gd for estimating Ki. 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 Kis 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 × 10−3 and 6.8 ± 3.5 × 10−3 ml.g−1 · min−1, respectively). In most instances, Gd‐DTPA MRI accurately localized areas of BBB opening. Magn Reson Med, 2005.

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, T1 and T2, and magnetization transfer (MT) related parameters (T1sat, Kfor 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 14C‐α‐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 T1sat 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 T1sat 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. Magn Reson Med, 2005.

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.

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.

Pathophysiology of migraine.

Publisher Summary This chapter discusses the mechanism of aura and head pain along with a discussion of interictal disturbances which lead to a propensity to developing migraine. Excitability of cell membranes, perhaps in part genetically determined, determines the brains susceptibility to attacks. Factors that increase or decrease neuronal excitability constitute the threshold for triggering attacks. Using a model of visual stress-induced migraine or by studying spontaneous attacks and applying advanced imaging and neurophysiological methods, results are obtained that support spreading neuronal inhibition as the basis of aura. This neuroelectrical event is accompanied by hyperoxia of the brain, possibly associated with vasodilation. Evidence is obtained that the spreading cortical event can activate subcortical centers possibly involved in nociception and associated symptoms of the migraine attack. Susceptibility to migraine attack appears related to brain hyperexcitability. Newer techniques of functional neuroimaging have confirmed the primary neural basis of the migraine attack with secondary vascular changes, reconciling previous theories into a neurovascular mechanism.

TH‐D‐AUD C‐01: Early Blood‐Brain‐Barrier Disruption in Response to RT as a Biomarker for Neurotoxicity

Purpose: Studies of neurocognitive dysfunction after radiation in animals suggest that vascular injury plays a key role. We hypothesized that blood‐brain‐barrier (BBB) disruption in normal appearing cerebral tissue of patients early in the course of fractionated radiation therapy (RT) is a biomarker for delayed neurocognitive dysfunction. Method and Materials: Ten patients with low‐grade glioma, or suprasellar lesion and underwent 3D conformal cranial RT (28–33 fx of 1.8 Gy) participated in a prospective MRI study. Dynamic‐contrast enhanced (DEC) MRI was acquired before, at week 3 and week 6 during the course of, and at 1, 6 and 18 months after the completion of RT. Using the modified Toft model, the contrast transfer constant (K) from the intravascular space to the extravascular extracellular space was estimated. A battery of standardized neuropsychological tests was performed at the same times as the pre‐ and post‐RT MRI. The relationship between the temporal changes in K and the dosimetric parameters was analyzed by a linear mixed model. Correlations between the changes in K and early delayed changes in the neurocognitve functions were analyzed by linear regression.Results: The K values increased significantly in normal appearing tissue regions that received >40 Gy at week 6 during RT (p<0.05), suggesting BBB opening. The elevated K values decreased gradually after RT. The changes in K both during and after RT were significantly correlated with the doses received at the time but the significance decreased from p = 0.0001 at week 3 during RT to 0.03 at 6 months after RT. The changes in K of left frontal lobe at week 3 during RT were significantly negatively correlated with the changes in verbal learning scores at 6 months after RT (p<0.02). Conclusion: Our data suggest early BBB disruption could be a biomarker for delayed neurocognitve function deterioration. Supported by NIHP01CA59827 and R21CA11369901.