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Integrin β1 receptor, expressed on the surface of tumor cells and macrophages in the tumor microenvironment (TME), has been implicated in both tumor progression and resistance to multiple modalities of therapy. OS2966 is the first clinical-ready humanized monoclonal antibody to block integrin β1 and was recently orphan designated by the FDA Office of Orphan Products Development. Here, we tested therapeutic potential of OS2966-mediated integrin β1 blockade to enhance the efficacy of oncolytic herpes simplex virus-1 (oHSV) through evaluation of virus replication, tumor cell killing efficiency, effect on the antiviral signaling pathway, co-culture assays of oHSV-infected cells with macrophages, and in vivo bioluminescence imaging on mammary fat pad triple-negative breast cancer xenograft and subcutaneous and intracranial glioma xenografts. OS2966 treatment decreased interferon signaling and proinflammatory cytokine induction in oHSV-treated tumor cells and inhibited migration of macrophages, resulting in enhanced oHSV replication and cytotoxicity. OS2966 treatment also significantly enhanced oHSV replication and oHSV-mediated antitumor efficacy in orthotopic xenograft models, including triple-negative breast cancer and glioblastoma. The results demonstrated the synergistic potential of the combinatory treatment approach with OS2966 to improve antitumor efficacy of conventional oHSV therapy., (©2019 American Association for Cancer Research.)

HMGB1 is a ubiquitously expressed intracellular protein that binds DNA and transcription factors and regulates chromosomal structure and function. Under conditions of cell death or stress, it is actively or passively released by cells into the extracellular environment, where it functions as damage-associated molecular pattern (DAMP) that orchestrates pro-inflammatory cytokine release and inflammation. Our results demonstrate that HMGB1 is secreted in the tumor microenvironment after oncolytic HSV (oHSV) infection in vitro and in vivo . The impact of secreted HMGB1 on tumor growth and response to oncolytic viral therapy was evaluated by using HMGB1-blocking antibodies in vitro and in mice bearing intracranial tumors. IVIS and MRI imaging was utilized to visualize in real time virus spread, tumor growth, and changes in edema in mice. Our data showed that HMGB1 released in tumor microenvironment orchestrated increased vascular leakiness and edema. Further HMGB1 blocking antibodies rescued vascular leakiness and enhanced survival of intracranial glioma-bearing mice treated with oHSV.

The effect of chronic cocaine exposure on multiple white matter structures in rodent brain was examined using diffusion tensor imaging (DTI), locomotor behavior, and end point histology. The animals received either cocaine at a dose of 100mg/kg (N=19), or saline (N=17) for 28 days through an implanted osmotic minipump. The animals underwent serial DTI scans, locomotor assessment, and end point histology for determining the expressions of myelin basic protein (MBP), neurofilament-heavy protein (NF-H), proteolipid protein (PLP), Nogo-A, aquaporin-4 (AQP-4), and growth associated protein-43 (GAP-43). Differences in the DTI measures were observed in the splenium (scc) and genu (gcc) of the corpus callosum (cc), fimbria (fi), and the internal capsule (ic). A significant increase in the activity in the fine motor movements and a significant decrease in the number of rearing events were observed in the cocaine-treated animals. Reduced MBP and Nogo-A and increased GAP-43 expressions were most consistently observed in these structures. A decrease in the NF-H expression was observed in fi and ic. The reduced expression of Nogo-A and the increased expression of GAP-43 may suggest destabilization of axonal connectivity and increased neurite growth with aberrant connections. Increased GAP-43 suggests drug-induced plasticity or a possible repair mechanism response. The findings indicated that multiple white matter tracts are affected following chronic cocaine exposure., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Ultrasound (U/S) and MRI measurements of the optic nerve sheath diameter (ONSD) have been proposed as intracranial pressure measurement surrogates, but these methods have not been fully evaluated or standardized. The purpose of this study was to develop an ex-vivo model for evaluating ONSD measurement techniques by comparing U/S and MRI measurements to physical measurements., Methods: The left eye of post mortem juvenile pigs (N = 3) was excised and the subdural space of the optic nerve cannulated. Caliper measurements and U/S imaging measurements of the ONSD were acquired at baseline and following 1 cc saline infusion into the sheath. The samples were then embedded in 0.5% agarose and imaged in a 7 Tesla (7T) MRI. The ONSD was subsequently measured with digital calipers at locations and directions matching the U/S and direct measurements., Results: Both MRI and sonographic measurements were in agreement with direct measurements. U/S data, especially axial images, exhibited a positive bias and more variance (bias: 1.318, 95% limit of agreement: 8.609) compared to MRI (bias: 0.3156, 95% limit of agreement: 2.773). In addition, U/S images were much more dependent on probe placement, distance between probe and target, and imaging plane., Conclusions: This model appears to be a valid test-bed for continued scrutiny of ONSD measurement techniques. In this model, 7T MRI was accurate and potentially useful for in-vivo measurements where direct measurements are not available. Current limitations with ultrasound imaging for ONSD measurement associated with image acquisition technique and equipment necessitate further standardization to improve its clinical utility.

Purpose: To characterize the influence of optical defocus on ocular shape and the pattern of peripheral refraction in infant rhesus monkeys., Methods: Starting at 3 weeks of age, eight infant monkeys were reared wearing -3 diopter (D) spectacle lenses over one eye that produced relative hyperopic defocus in the nasal field (NF) but allowed unrestricted vision in the temporal field (NF group). Six infants were reared with monocular -3 D lenses that produced relative hyperopic defocus across the entire field of view. Control data were obtained from 11 normal monkeys. Refractive development was assessed by streak retinoscopy performed along the pupillary axis and at eccentricities of 15 degrees, 30 degrees, and 45 degrees along the vertical and horizontal meridians. Central axial dimensions and eye shape were assessed with magnetic resonance imaging., Results: In response to full-field hyperopic defocus, the eye developed relative central axial myopia, became less oblate, and exhibited relative peripheral hyperopia in both the nasal and the temporal hemifields. Conversely, nasal-field hyperopic defocus produced relative myopia that was largely restricted to the nasal hemifield; these alterations in the patterns of peripheral refraction in the NF monkeys were associated with local, region-specific alterations in vitreous chamber depth in the treated hemiretina., Conclusions: Optically imposed defocus can alter the shape and pattern of peripheral refraction in infant primates. Like those of form deprivation, the effects of optical defocus in primates are dominated by mechanisms that integrate visual signals in a spatially restricted manner and exert their influence in a regionally selective manner.

Perinatal hypoxia affects normal neurological development and can lead to motor, behavioral and cognitive deficits. A common acute treatment for perinatal hypoxia is oxygen resuscitation (hyperoximia), a controversial treatment. Magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI), was performed in a P7 rat model of perinatal hypoxia to determine the effect of hyperoximia. These studies were performed on two groups of animals: 1) animals which were subjected to ischemia followed by hypoxia (HI), and 2) HI followed by hyperoximic treatment (HHI). Lesion volumes on high resolution MRI and DTI derived measures, fractional anisotropy (FA), mean diffusivity (MD), and axial and radial diffusivities (lambda(l) and lambda(t), respectively) were measured in vivo one day, one week, and three weeks after injury. Most significant differences in the MRI and DTI measures were found at three weeks after injury. Specifically, three weeks after HHI injury resulted in significantly larger hyperintense lesion volumes (95.26 +/- 50.42 mm(3)) compared to HI (22.25 +/- 17.62 mm(3)). The radial diffusivity lambda(t) of the genu of corpus callosum was significantly larger in HHI (681 +/- 330 x 10(-6) mm(2)/sec) than in HI (486 +/- 96 x 10(-6) mm(2)/sec). Over all, most significant differences in all the DTI metrics (FA, MD, lambda(t), lambda(l)) at all time points were found in the corpus callosum. Our results suggest that treatment of perinatal hypoxia with normobaric oxygen does not ameliorate, but exacerbates damage., ((c) 2009 Wiley-Liss, Inc.)

Purpose: To determine whether refractive development in primates is mediated by local retinal mechanisms, the authors examined the effects of hemiretinal form deprivation on ocular growth and the pattern of peripheral refractions in rhesus monkeys., Methods: Beginning at approximately 3 weeks of age, nine infant monkeys were reared wearing monocular diffuser lenses that eliminated form vision in the nasal field (nasal field diffuser [NFD]). Control data were obtained from the nontreated fellow eyes, 24 normal monkeys, and 19 monkeys treated with full-field diffusers. Refractive development was assessed by retinoscopy performed along the pupillary axis and at eccentricities of 15 degrees, 30 degrees, and 45 degrees. Central axial dimensions and eye shape were assessed by A-scan ultrasonography and magnetic resonance imaging, respectively., Results: Hemiretinal form deprivation altered refractive development in a regionally selective manner, typically producing myopia in the treated hemifields. In particular, six of the NFD monkeys exhibited substantial amounts (-1.81 to -9.00 D) of relative myopia in the nasal field that were most obvious at the 15 degrees and 30 degrees nasal field eccentricities. The other three NFD monkeys exhibited small amounts of relative hyperopia in the treated field. The alterations in peripheral refraction were associated with local, region-specific alterations in vitreous chamber depth in the treated hemiretina., Conclusions: The effects of form deprivation on refractive development and eye growth in primates are mediated by mechanisms, presumably retinal, that integrate visual signals in a spatially restricted manner and exert their influence locally.

Purpose: To determine whether visual experience can alter ocular shape and peripheral refractive error pattern, the authors investigated the effects of form deprivation on refractive development in infant rhesus monkeys., Methods: Monocular form deprivation was imposed in 10 rhesus monkeys by securing diffuser lenses in front of their treated eyes between 22 +/- 2 and 163 +/- 17 days of age. Each eye's refractive status was measured longitudinally by retinoscopy along the pupillary axis and at 15 degrees intervals along the horizontal meridian to eccentricities of 45 degrees . Control data for peripheral refraction were obtained from the nontreated fellow eyes and six untreated monkeys. Near the end of the diffuser-rearing period, the shape of the posterior globe was assessed by magnetic resonance imaging. Central axial dimensions were also determined by A-scan ultrasonography., Results: Form deprivation produced interocular differences in central refractive errors that varied between +2.69 and -10.31 D (treated eye-fellow eye). All seven diffuser-reared monkeys that developed at least 2.00 D of relative central axial myopia also showed relative hyperopia in the periphery that increased in magnitude with eccentricity. Alterations in peripheral refraction were highly correlated with eccentricity-dependent changes in vitreous chamber depth and the shape of the posterior globe., Conclusions: Like humans with myopia, monkeys with form-deprivation myopia exhibit relative peripheral hyperopia and eyes that are less oblate and more prolate. Thus, in addition to producing central refractive errors, abnormal visual experience can alter the shape of the posterior globe and the pattern of peripheral refractive errors in infant primates.

Perinatal hypoxia is a major cause of neurodevelopmental deficits. Neuronal migration patterns are particularly sensitive to perinatal hypoxia/ischemia and are associated with the clinical deficits. The rat model of hypoxia/ischemia at P7 mimics that of perinatal injury in humans. Before assessing the effects of postnatal injury on brain development, it is essential to determine the normal developmental trajectories of various brain structures in individual animals. In vivo longitudinal diffusion tensor imaging (DTI) was performed from postnatal day 0 (P0) to P56 on Wistar rats. The DTI metrics, mean diffusivity (MD), fractional anisotropy (FA), axial (lambdal) and radial (lambdat) diffusivities, were determined for four gray matter and eight white matter structures. The FA of the cortical plate and the body of corpus callosum decreased significantly during the first 3 weeks after birth. The decrease in the cortical plate's FA value was associated mainly with an increase in lambdat. The initial decrease in FA of corpus callosum was associated with a significant decrease in lambdal. The FA of corpus callosum increased during the rest of the observational period, which was mainly associated with a decrease in lambdat. The FA of gray matter structures, hippocampus, caudate putamen, and cortical mantle did not show significant changes between P0 and P56. In contrast, the majority of white matter structures showed significant changes between P0 and P56. These temporal changes in the DTI metrics were related to the neuronal and axonal pruning and myelination that are known to occur in the developing brain.

Functional magnetic resonance imaging (fMRI) studies were performed for visualizing ongoing brain plasticity in Neurotrophin-3 (NT3)-treated experimental spinal cord injury (SCI). In response to the electrical stimulation of the forepaw, the NT3-treated animals showed extensive activation of brain structures that included contralateral cortex, thalamus, caudate putamen, hippocampus, and periaqueductal gray. Quantitative analysis of the fMRI data indicated significant changes both in the volume and center of activations in NT3-treated animals relative to saline-treated controls. A strong activation in both ipsi- and contralateral periaqueductal gray and thalamus was observed in NT3-treated animals. These studies indicate ongoing brain reorganization in the SCI animals. The fMRI results also suggest that NT3 may influence nociceptive pathways.

Background and Purpose: High-resolution, vascular MR imaging of the spine region in small animals poses several challenges. The small anatomic features, extravascular diffusion, and low signal-to-noise ratio limit the use of conventional contrast agents. We hypothesize that a long-circulating, intravascular liposomal-encapsulated MR contrast agent (liposomal-Gd) would facilitate visualization of small anatomic features of the perispinal vasculature not visible with conventional contrast agent (gadolinium-diethylene-triaminepentaacetic acid [Gd-DTPA])., Methods: In this study, high-resolution MR angiography of the spine region was performed in a rat model using a liposomal-Gd, which is known to remain within the blood pool for an extended period. The imaging characteristics of this agent were compared with those of a conventional contrast agent, Gd-DTPA., Results: The liposomal-Gd enabled acquisition of high quality angiograms with high signal-to-noise ratio. Several important vascular features, such as radicular arteries, posterior spinal vein, and epidural venous plexus were visualized in the angiograms obtained with the liposomal agent. The MR angiograms obtained with conventional Gd-DTPA did not demonstrate these vessels clearly because of marked extravascular soft-tissue enhancement that obscured the vasculature., Conclusions: This study demonstrates the potential benefit of long-circulating liposomal-Gd as a MR contrast agent for high-resolution vascular imaging applications.

Functional MRI (fMRI) on spinal cord-injured rodents at 4 and 8 weeks post injury (PI) is described. The paradigm for fMRI, based on electrical stimulation of rat paws, was automated using an in-house designed microprocessor-based controller that was interfaced to a stimulator. The MR images were spatially normalized to the Paxinos and Watson atlas using publicly available digital images of the cryosections. In normal uninjured animals, the activation was confined to the contralateral somatosensory cortex. In contrast, in injured animals, extensive activation, which included structures such as ipsilateral cortex, thalamus, hippocampus, and the caudate putamen, was observed at 4 and 8 weeks PI. Quantitative cluster analysis was carried out to calculate the volumes and centers of activation in individual brain structures. Based on this analysis, significant increase in activation between 4 and 8 weeks was observed only in the ipsilateral caudate putamen and thalamus. These studies suggest extensive and ongoing brain reorganization in spinal cord-injured animals., (Copyright 2006 Wiley-Liss, Inc.)

Cortical spreading depression (CSD) was induced by transient (10 min) applications of KCl in agar upon the cortical surface of alpha-chloralose anaesthetised cats. Its features were compared with CSD resulting from sustained applications of crystalline KCl through a mapping of the apparent diffusion coefficient (ADC) using diffusion-weighted echo planar imaging (DWI) over a poststimulus period of 60-100 min. Individual CSD events were computationally detected with the aid of Savitzky-Golay smoothing applied to critically sampled data derived from regions of interest (ROIs) made up of 2 x 2 pixel matrices. The latter were consistently placed at three selected sites on the suprasylvian gyrus (SG) and six sites on the marginal gyrus (MG). The CSD events thus detected were then quantitatively characterised for each ROI using the original time series. Both stimuli consistently elicited similar spreading patterns of initial, primary CSD events that propagated over the SG and marginal MG and were restricted to the hemispheres on which the stimuli were applied. There followed secondary events over smaller extents of cortical surface. Sustained stimuli elicited primary and secondary CSD events with similar amplitudes of ADC deflection that were distributed around a single mean. The ADC deflections were also conserved in peak amplitude throughout the course of their propagation. The initial primary event showed a poststimulus latency of 1.1 +/- 0.1 min. Successive secondary events followed at longer, but uniform, time intervals of around 10 min. Primary and secondary CSDs showed significantly different velocities of conduction (3.32 +/- 0.43 mm min(-1) vs. 2.11 +/- 0.21 mm min(-1), respectively; n = 5) across the cerebral hemisphere. In contrast, transient stimuli produced significantly fewer numbers of CSD events (3.8 +/- 0.5 events per animal, n = 5) than did sustained stimuli (7.4 +/- 0.5 events per animal, mean +/- S.E.M., n = 5, P = 0.002). The peak ADC deflection of their primary CSD events declined by approximately 30 % as they propagated from their initiation site to the interhemispheric boundary. The primary CSD event following a transient stimulus showed a latency of 1.4 +/- 0.1 min. It was followed by successive and smaller secondary ADC deflections that were separated by progressively longer time intervals. Conduction velocities of secondary events were similar to those of primary events. Conduction velocities of both primary and secondary events were slower than their counterparts following a sustained stimulus. ADC changes associated with CSD thus persist at times well after stimulus withdrawal and vary markedly with the nature of the initiating stimulus even in brain regions remote from the stimulus site.

Spreading cortical depolarization and depression of electroencephalographic activity (SD) may underlie the aura and spreading neurovascular events of migraine. Cortical depolarization may also precipitate the progressive development of cerebral pathology following ischemia. However, data on SD in the human brain are sparse, most likely reflecting the technical difficulties involved in performing such clinical studies. We have previously shown that the transient cerebral water disturbances during SD can be quantitatively investigated in the gyrencephalic brain using repetitive diffusion-weighted magnetic resonance imaging (DWI). To investigate whether DWI could detect modulation of the spatiotemporal properties of SD in vivo, the effects of the antimigraine drug sumatriptan (0.3 mg/kg iv) and the novel anticonvulsant tonabersat (10 mg/kg ip) were evaluated in the cat brain. Supporting previous findings, sumatriptan did not affect the numbers of events (range, 4-8), the duration of SD activity (39.8 +/- 4.4 min, mean +/- SEM), and event velocity (2.2 +/- 0.4 mm min(-1)); tonabersat significantly reduced SD event initiation (range, 0-3) and duration (13.2 +/- 5.0 min) and increased primary event velocity (5.4 +/- 0.7 mm min(-1)). However, both drugs significantly decreased, by >50%, the spatial extent of the first KCl-evoked SD event, and sumatriptan significantly increased event propagation across the suprasylvian sulcus (5.5 +/- 0.6 vs 2.4 +/- 0.4 events in controls). These results demonstrate (1) the feasibility of using DWI to evaluate therapeutic effects on SD, and (2) that sumatriptan may directly modulate the spatial distribution of SD activity in the gyrencephalic brain., ((c)2001 Elsevier Science.)

Cortical spreading depression (CSD) and peri-infarct depolarisation (PID) are related phenomena that have been associated with the human clinical syndromes of migraine (CSD), head injury and stroke (PID). Nevertheless the existence of CSD in man remains controversial, despite the detection of this phenomenon in the brains of most, if not all, other animal species investigated. This failure to unambiguously detect CSD clinically may be at least partly due to the anatomically complex, gyrencephalic structure of the human brain. This study was designed to establish conditions for the study of CSD in the brain of a gyrencephalic species using the noninvasive technique of magnetic resonance imaging (MRI). The 3-dimensional (3D) gyrencephalic anatomy of the cat brain was examined to determine the imaging conditions necessary to detect CSD events. Orthogonal transverse, sagittal and horizontal T1-weighted image slices showed that the marginal and suprasylvian gyri were the most appropriate cortical structures to study CSD. This was in view of (1) their simple geometry: (2) their lengthy extent of grey matter orientated rostrocaudally in the cortex: (3) their separation by a sulcus across which CSD spread could be studied and (4) the discontinuity in the grey matter in these regions between the right and left hemispheres dorsal to the corpus callosum. The structure suggested by the T1-weighted images was corroborated by systematic diffusion tensor imaging to map the fractional anisotropy and diffusion trace. Thus a single horizontal image plane could visualise the neighbouring suprasylvian and marginal gyri of both cerebral hemispheres, whereas its complex shape and position ruled out the ectosylvian gyrus for CSD studies. With the horizontal imaging plane, CSD events were reproducibly detected by animating successive diffusion-weighted MR images following local KCl stimulation of the cortical surface. In single image frames, CSD detection and characterisation required image subtraction or statistical mapping methods that, nevertheless, yielded concordant results. In repeat experiments, CSD events were qualitatively similar in appearance whether elicited by sustained or transient KCl applications. Our experimental approach thus successfully describes cat brain anatomy in vivo, and elucidates the necessary conditions for the application of MRI methods to detect CSD propagation.

Cortical spreading depression (CSD) in the gyrencephalic cat brain was detected with diffusion-weighted echoplanar (DWEP) magnetic resonance imaging (4-8/min for 1-2 hours) using a horizontal imaging plane through the suprasylvian (SG) and marginal gyri. A t-statistic mapping technique allowed a quantitative characterization of the passage of events through single-image pixels (0.15 mm(2)), thus providing a resolution unavailable to previous studies in which time-dependent changes instead were derived from averaging data over relatively large ROIs. Using the enhanced analysis, CSD events initiated by KCl could be quantified for the first time as primary or secondary according to their spatial and temporal features. Primary events covered 26.2 +/- 9.9 mm(2)of cortical surface (mean +/- SD, n = 7 experiments) and propagated rapidly (3.5 +/- 0.65 mm * min(-1)) with a hemispherical geometry. In contrast, the subsequent secondary events were multiple, spatially restricted (covering 7.6 +/- 4.6 mm(2), P < 0.005), slower in propagation (2.6 +/- 0.41 mm * min(-1), P < 0.012), and often confined to the originating gyrus (26 out of 59 events). However, both event types were associated with significantly reduced apparent diffusion coefficients (ADCs; from 800 to approximately 660 x 10(-6) mm(2)* s(-1), P < 0.05) that were similar for both primary (21 +/- 5.1%) and secondary waves (18 +/- 7. 7%) and that had similar durations (full width at half-maximal height: 86 +/- 17 vs. 79 +/- 20 seconds, respectively). These findings associate CSD for the first time with two categories of ADC disturbance that are similar in amplitude and duration but that differ in spatial extent, velocity, and extensiveness of spread.

1.Time-lapse diffusion-weighted magnetic resonance imaging (DWI) was used to detect and characterize complex waves of cortical spreading depression (CSD) evoked with KCL placed upon the suprasylvian gyrus of anaesthetized cats. 2. The time-lapse representations successfully demonstrated primary CSD waves that propagated with elliptical wavefronts selectively over the ipsilateral cerebral hemispheres with a velocity of 3.8 +/- 0.70 mm min(-1) (mean +/- S.E.M. of 5 experiments). 3. In contrast, the succeeding secondary waves often remained within the originating gyrus, were slower (velocity 2.0 +/- 0.18 mm min(-1), more fragmented and varied in number. 4. Computed traces of the apparent diffusion coefficients (ADCs) showed negative deflections followed by monotonic decays (amplitudes: primary wave, -19.9 +/- 2.8%; subsequent waves, -13.6 +/- 1.9% duration at half-maximal decay, 150-200 s) when determined from regions of interest (ROIs) through which both primary and succeeding CSD waves propagated. 5. The passage of both the primary and the succeeding waves often correlated with transient DC potential deflections recorded from the suprasylvian gyrus. 6. The detailed waveforms of the ADC and the T2*-weighted (blood oxygenation level-dependent: BOLD) traces showed a clear reciprocal correlation. These imaging features that reflect disturbances in cellular water balance agree closely with BOLD measurements that followed the propagation velocities of the first and subsequent CSD events. They also provide a close physiological correlate for clinical observations of cortical blood flow disturbances associated with human migraine.

Objective: Our aim was to assess the correlation between the low-grade glioma (LGG) metabolic profile and tumor progression. Using in vivo proton magnetic resonance spectroscopic imaging, we specifically asked whether and which metabolic features are associated with tumor regrowth or recurrence., Methods: Eleven pediatric patients with histologically proven partially resected (<20% resection) midline LGG were treated and followed up for a period of 2 years. All patients underwent proton magnetic resonance spectroscopic imaging studies before any management was determined. Tumor progression was defined as radiological evidence of mass enlargement (>25%) during the follow-up period. Proton magnetic resonance spectroscopic imaging was performed using a PRESS-CSI sequence on a General Electric 1.5-tesla scanner (General Electric Medical System, Waukesha, WI). The signal intensities of N-acetylaspartate, choline (CHO), and creatine from the tumor and the normal brain were used to calculate normalized metabolite intensities and metabolite ratios., Results: Tumors that progressed during a 2-year period displayed higher normalized CHO than those that remained stable (Mann-Whitney test, P < 0.03). The majority (five of six) of the rapidly growing LGG showed values of normalized CHO of at least 1, whereas the nonprogressors had a normalized CHO value of less than 1., Conclusion: In association with pediatric LGG, high normalized CHO values seem to herald the potential for rapid tumor growth. These observations may be valuable for defining subsets of patients with LGG who may benefit from early therapeutic interventions.

Despite their uniform histologic appearance, pediatric low-grade astrocytomas (LGA) often exhibit a rather unpredictable clinical course. It is presently unclear whether certain specific genetic, immunologic and/or metabolic features underlie these observed variations. In order to address this question we examined the tumor distribution of choline compounds (Cho), creatine (Cr) and N-acetyl aspartate (NAA) in seven children with midline LGA by means of proton magnetic resonance spectroscopy imaging (H-MRSI). Studies were performed with a 1.5 T GE Signa Scanner equipped with the standard head coil; nominal voxel size was 7.5 x 7.5 x 15 mm. This spatial resolution allowed us to select and independently evaluate multiple regions of interest (ROI) in the tumor as well as in areas of normal brain from the same individual. Normalized values of the observed signal intensities demonstrated a lower NAA and Cr content in the tumors than in the surrounding normal brain. Intratumoral Cho signals were also below normal values in all but one patient. The average Cho:NAA ratio was consistently higher in the tumor than in the normal brain. However, there was a wide variation (up to fourfold) in the Cho:NAA ratios of different ROIs, even within the same tumor. Our results clearly indicate that pediatric LGAs are metabolically heterogeneous, a feature that may be relevant to the understanding of their variable biologic behavior. Inasmuch as unique metabolic patterns were observed in some LGAs, we believe that systematic HMRSI studies of these patients may help define subsets within the group with specific therapeutic requirements.

The purpose of the study was to determine whether diffusion-weighted magnetic resonance imaging (DWI) could identify focal lesions that develop in ischemia-sensitive cerebral tissues during reperfusion following global brain ischemia. Localized 1H-Magnetic Resonance Spectroscopy (1H-MRS) measurements were also obtained to determine whether abnormal spectroscopic markers were associated with focal lesions and to define time correlations between DWI and metabolic changes. Brain diffusion-weighted magnetic resonance imaging measurements were made in a cat model of repetitive global cerebral ischemia and reperfusion. Five animals were exposed to three episodes of 10 min vascular occlusions at hourly intervals. Three animals were evaluated as controls. DWI, T2WI, and 1H-MRS data were acquired for up to 12 h. Transient focal DWI hyperintensity was detected in the hippocampus, basal ganglia, and cortical watershed areas. These focal abnormalities usually appeared during the final reperfusion and eventually spread to encompass all of the gray matter. Spectroscopic measurements demonstrated the expected elevation of the lactate signal intensity during vessel occlusion, which returned to normal during early reperfusion. A subsequent rise in the lactate signal occurred approximately 3-4 h after the beginning of the third reperfusion. This late lactate elevation occurred after focal hyperintensities were identified by DWI. No significant signal changes were seen in spectroscopic metabolites other than lactate. The study illustrates that DWI and 1H-MRS are sensitive to focal cerebral lesions that occur during reperfusion following global cerebral ischemia.