Hepatic 31P MRS in rat models of chronic liver disease: assessing the extent and progression of disease.

BACKGROUND: Hepatic adenosine triphosphate (ATP) levels are an accurate reflection of functioning hepatic mass following surgical resections and acute liver injury. OBJECTIVE: To determine whether hepatic ATP levels can serve as a non-invasive means of documenting progression of chronic liver disease to cirrhosis. METHODS: In vivo phosphorus-31 magnetic resonance spectroscopy ((31)P MRS) was performed in three animal models of chronic liver disease. Sixty six adult Sprague- Dawley rats were subjected to either thioacetamide, carbon tetrachloride (CCl(4)), or common bile duct ligation (CBDL) to induce liver disease (n=35, 21, and 10, respectively). Serial MRS examinations, blood samples, and liver biopsies (when appropriate) were obtained throughout and/or on completion of the study. RESULTS: Over the course of the chronic liver disease, a progressive decrease in hepatic ATP levels was consistently observed in each model. The findings were most striking when end stage liver disease (cirrhosis) was established. The reduction in hepatic ATP levels correlated with significant changes in serum albumin concentrations (CCl(4) and CBDL models) and the extent of hepatocyte loss seen histologically (all models). CONCLUSION: The results of this study indicate that during progression of chronic liver disease to cirrhosis, there is a progressive reduction in hepatic ATP levels. In addition, changes in hepatic ATP levels correlate with changes in liver function and histology. Thus hepatic (31)P MRS provides a non-invasive means of documenting the severity and progression of parenchymal and cholestatic models of chronic liver disease in rats.

Neurovirulence depends on virus input titer in brain in feline immunodeficiency virus infection: evidence for activation of innate immunity and neuronal injury.

Lentiruses cause neurological disease depending on the virus strain and its neurotropism, yet it remains uncertain to what the impact of infectious virus quantity in the brain early in infection is on the subsequent development of neurological disease or neurovirulence. We investigated the relationship between infectious virus input titer and the resulting neurovirulence, using ex vivo and in vivo assays of feline immunodeficiency virus (FIV)-induced neurovirulence. FIV infection of cell cultures and neonatal cats was performed using 10(2.5) (low-titer) or 10(4.5) (high-titer) 50% tissue culture infectious doses (TCID(50))/ml of the neurovirulent FIV strain, V1CSF. Ex vivo neurotoxicity assays revealed that conditioned medium (CM) from feline macrophages infected with high-titer (P <.001) or low-titer (P <.01) V1CSF induced greater neuronal death than CM from mock-infected cells. In vivo, animals infected intracranially with high-titer V1CSF showed neurodevelopmental delays compared to mock-infected animals (P <.001) and animals infected with low-titer V1CSF (P <.02), concurrent with reduced weight gains and greater depletion of CD4+ cells over a 12-week period. Neuropathological changes, including astrogliosis, macrophage activation, and neuronal damage, were evident in V1CSF-infected animals and were viral titer dependent. In vivo magnetic resonance (MR) spectroscopy and proton nuclear magnetic resonance ((1)H-NMR) spectroscopy of tissue extracts revealed evidence of neuronal injury, including reduced N-acetyl aspartate/creatine (P <.05) and increased trimethylamine/creatine (P <.05) ratios, in the frontal cortex of high-titer V1CSF-infected animals compared to the other groups. T2-weighted MR imaging detected increased signal intensities in the frontal cortex and white matter of V1CSF-infected animals relative to controls, which was more evident as viral titer increased (P <.01). The present findings indicate that lentivirus infectious titers in the brain during the early stages of infection determine the severity of neurovirulence, reflected by neurobehavioral deficits, together with neuroradiological and neuropathological findings of activation of innate immunity and neuronal injury.

A serial MR study of cerebral blood flow changes and lesion development following endothelin-1-induced ischemia in rats.

The vasoconstrictive peptide endothelin-1 (ET-1) has been used previously to transiently occlude the middle cerebral artery (MCA) in rats. However, the duration of the resulting reduction in cerebral blood flow (CBF) and the reperfusion characteristics are poorly understood. In this study perfusion and T(2)-weighted MRI were used together with histology to characterize the cerebral perfusion dynamics and lesion development following ET-1 injection. Twenty-two rats received an intracerebral injection of ET-1 adjacent to the MCA. CBF was reduced to 30-50% of control levels, and a significant reduction persisted for 16 h in the cortex and 7 h in the striatum. The lesion size measured by T(2)-weighted imaging at 48 h correlated with the final infarct size measured by histology at 7 d. The sustained reduction in CBF and the gradual development of the ischemic lesion resemble human stroke evolution, suggesting that this model may be useful for evaluating therapeutic agents, particularly when treatment is delayed.

T2-weighted MRI correlates with long-term histopathology, neurology scores, and skilled motor behavior in a rat stroke model.

The intraluminal suture model of transient middle cerebral artery occlusion (MCAO) in the Sprague Dawley strain of rats characteristically results in an inconsistently sized brain lesion. The purpose of the investigation reported here was to determine whether there were strong point-to-point correlations between the degree of cortical lesion size, as assessed in vivo using T2-weighted magnetic resonance imaging (MRI) and corresponding cortical lesion size using routine histopathological techniques. Moreover, we aimed to investigate if cortical lesion size as determined by these two modalities correlates with neurological and/or skilled motor deficits observed in individual animals. Baseline behavioral scores were obtained on the animals prior to receiving 60 min of transient MCAO. Following MCAO, animals were tested for 1-21 days for neurological deficits. T2-weighted MRIs of the cortex were taken at two and seven days post-MCAO. At 30 and 60 days the rats were retested for forelimb dexterity in the staircase test. Subsequently, the cortex was examined for histopathological damage. Indeed, there were highly significant correlations between lesion size determined by MRI and histopathology. The degree of cortical damage observed in the T2-weighted MRI, as well as the size of the histopathological lesions were, in turn, highly correlated with the degrees of deficiencies observed in the composite neurological assessments and with the deficits involving skilled use of the contralateral forepaw (damaged side).

Adenosine A2A receptor activation reduces proinflammatory events and decreases cell death following intracerebral hemorrhage.

The ubiquitous neuromodulator adenosine inhibits the production of several proinflammatory cytokines through activation of specific cell-surface adenosine receptors. We demonstrated recently that antisense oligonucleotides to tumor necrosis factor-alpha (TNF-alpha) are neuroprotective in a rat model of intracerebral hemorrhage. Therefore, we hypothesized that activation of adenosine receptors would provide protection against intracerebral hemorrhage-induced TNF-alpha production and inflammatory events. In vitro experiments showed that adenosine A1, A2A, and A3 receptor subtypes were present on U937 cells, and activation of these subtypes inhibited TNF-alpha production with a rank order of A2A > > A1 > A3. Prolonged treatment of U937 cells with the A2A receptor agonist 2-p-(carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680) desensitized adenosine A2A, A1, and A3 receptors. CGS 21680 administration directly into the striatum immediately prior to the induction of intracerebral hemorrhage inhibited TNF-alpha mRNA and, 24 hours following induction, reduced parenchymal neutrophil infiltration (p < 0.001) and TUNEL-positive cells (p < 0.002) within and bordering the hematoma. These results suggest that pharmacological strategies targeting A2A receptors may provide effective inhibition of acute neurotoxic proinflammatory events that occur following intracerebral hemorrhage.

Efficacy of disodium 4-[(tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (NXY-059), a free radical trapping agent, in a rat model of hemorrhagic stroke.

Because free radical mechanisms may contribute to brain injury in hemorrhagic stroke, the effect of the free radical trapping agent disodium 4-[(tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (NXY-059) was investigated on outcome following intracerebral hemorrhage (ICH) in rat. ICH was induced in 20 adult rats by infusion of collagenase into the caudate-putamen. Thirty minutes later rats were treated with NXY-059 (50 mg/kg subcutaneous plus 8.8 mg/kg/h for 3 days subcutaneous delivered via implanted osmotic pumps) or saline (equivalent volumes). Magnetic resonance imaging 24 h after ICH confirmed that the hemorrhage was uniform in the two groups, and subsequent imaging at 7 and 42 days post-ICH showed that the hematoma resolved similarly in the two groups. Behavioral testing on days 1, 3, 7, 14, and 21 after ICH showed that rats treated with NXY-059 had significantly decreased neurological impairment at all times. Deficits in skilled forelimb use 4-5 weeks post-ICH, and in striatal function 6 weeks post-ICH, were not reduced by treatment with NXY-059. Treatment with NXY-059 significantly reduced the neutrophil infiltrate observed 48 h post-hemorrhage in the vicinity of the hematoma, and the number of TUNEL-positive cells 48 h post-hemorrhage at the hematoma margin. However, by 6 weeks there were no differences in neuronal densities in treated and control rats.

Effect of FK-506 on inflammation and behavioral outcome following intracerebral hemorrhage in rat.

Beginning 15 min after induction of intracerebral hemorrhage (ICH) by intrastriatal administration of collagenase, rats were treated intramuscularly with FK-506 (3 mg/kg) or with vehicle. Treatment was repeated daily for 7 days. MR imaging 1, 7, and 28 days post-ICH showed that treatment did not affect hematoma size or its subsequent resolution. Two days post-ICH, neutrophil infiltration around the hematoma was decreased in the FK-506-treated rats, as was the number of TUNEL-positive cells at the edge of the hematoma and in the peripheral region. The decreased inflammatory response was accompanied by functional improvement in the treated rats. The neurological deficit induced by the ICH (beam walking ability, postural reflex, spontaneous circling) was significantly decreased from 3 to 21 days post-ICH by treatment with FK-506. Skilled use of the forelimb ipsilateral to the ICH was improved and sensory neglect of the same limb was decreased 8-9 weeks post-ICH in rats treated with FK-506. However, neuronal loss assessed 9 weeks post-ICH was not different in the treated and untreated rats.

Antisense oligodeoxynucleotide inhibition of tumor necrosis factor-alpha expression is neuroprotective after intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Tumor necrosis factor-alpha (TNF-alpha) expression is increased in brain after cerebral ischemia, although little is known about its abundance and role in intracerebral hemorrhage (ICH). A TNF-alpha-specific antisense oligodeoxynucleotide (ORF4-PE) was used to study the extent to which TNF-alpha expression influenced neurobehavioral outcomes and brain damage in a collagenase-induced ICH model in rat. METHODS: Male Sprague-Dawley rats were anesthetized, and ICH was induced by intrastriatal administration of heparin and collagenase. Immediately before or 3 hours after ICH induction, ORF4-PE was administered directly into the site of ICH. TNF-alpha mRNA and protein levels were measured by reverse transcriptase-polymerase chain reaction and immunoblot analyses. Cell death was measured by terminal deoxynucleotidyl transferase-mediated uridine 5'triphosphate-biotin nick end labeling (TUNEL). Neurobehavioral deficits were measured for 4 weeks after ICH. RESULTS: ICH induction (n=6) elevated TNF-alpha mRNA and protein levels (P:<0.01) at 24 hours after the onset of injury compared with sham controls (n=6). Immunohistochemical labeling indicated that ICH was accompanied by elevated expression of TNF-alpha in neutrophils, macrophages, and microglia. Administration of ORF4-PE (2.0 nmol) directly into striatal parenchyma, 15 minutes before (n=4) or 3 hours after (n=6) ICH, decreased levels of TNF-alpha mRNA (P:<0.001) and protein (P:<0. 01) in the brain tissue surrounding the hematoma compared with animals treated with saline alone (n=6). Mean+/-SEM striatal cell death (cells per high-powered field) was also reduced in animals receiving ORF4-PE (34.1+/-5.0) compared with the saline-treated ICH group (80.3+/-7.50) (P:<0.001). ORF4-PE treatment improved neurobehavioral deficits observed at 24 hours (P:<0.001) after induction of ICH (n=6) compared with the untreated ICH group (n=6). This improvement was maintained at 28 days after hemorrhage induction (P:<0.001). CONCLUSIONS: These results indicate a pathogenic role for TNF-alpha during ICH and demonstrate that reducing TNF-alpha expression using antisense oligodeoxynucleotides is neuroprotective.

Rat middle cerebral artery occlusion: correlations between histopathology, T2-weighted magnetic resonance imaging, and behavioral indices.

During attempts to develop the intraluminal suture model of transient middle cerebral artery occlusion (MCAO) in the Sprague Dawley strain of rats, we noticed a wide variability in lesion size seen with T2-weighed magnetic resonance imaging (MRI) or histopathology, as well as in scores for behavioral indices. It was our intent to examine the results of the study carefully and determine whether there were strong point-to-point correlations between the degree of lesion size determined from T2-weighted MRI or histopathology and intermediate or long-term neurologic/behavioral assessments. Baseline behavioral scores for forelimb dexterity (staircase test) were obtained on all animals in the period before receiving 60 minutes of transient MCAO. After MCAO, animals were tested at specified intervals from 1 to 21 days for composite neurologic deficits. T2-weighted MRI was taken at 2 and 7 days post-MCAO. At 30 and 60 days post-MCAO, animals were retested in the staircase test with subsequent histopathologic examination of the brains. Indeed, there were highly significant correlations between lesion size determined by MRI and histopathology. The damage observed in the T2-weighted MRI, as well as the size of the histopathologic lesions, were in turn highly correlated to deficiencies observed in the composite neurologic assessments, as well as to deficits at 30 and 60 days post-MCAO for skilled use of the contralateral forepaw (damaged side). In the latter test, the correlations were somewhat less significant for the ability of rats to reach for food with the ipsilateral forepaw (undamaged side).

Dietary betaine modifies hepatic metabolism but not renal injury in rat polycystic kidney disease.

We undertook a morphometric and proton nuclear magnetic resonance ((1)H-NMR) study to test the hypothesis that 1% dietary betaine supplementation would ameliorate renal disease in the heterozygous Han:SPRD-cy rat, a model of polycystic kidney disease (PKD) and progressive chronic renal failure. After 8 wk of pair feeding, betaine had no effect on renal cystic change, renal interstitial fibrosis, serum creatinine, serum cholesterol, or serum triglycerides. (1)H-NMR spectroscopy of renal tissue revealed no change in renal osmolytes, including betaine, or renal content of other organic anions in response to diet. (1)H-NMR spectroscopy of hepatic tissue performed to explore the metabolic fate of ingested betaine revealed that heterozygous animals fed the control diet had elevated hepatic levels of gluconeogenic amino acids, increased beta-hydroxybutyrate, and increased levels of some citric acid cycle metabolites compared with animals without renal disease. Betaine supplementation eliminated these changes. Chronic renal failure in the Han:SPRD-cy rat is associated with disturbances of hepatic metabolism that can be corrected with betaine therapy, suggesting the presence of a reversible methylation defect in this form of chronic renal failure.

Effects of nitrobenzylthioinosine on neuronal injury, adenosine levels, and adenosine receptor activity in rat forebrain ischemia.

Adenosine levels increase in brain during cerebral ischemia, and adenosine has receptor-mediated neuroprotective effects. This study was performed to test the hypothesis that nitrobenzylthioinosine (NBMPR), a selective and potent inhibitor of one adenosine transporter subtype termed ENT1, or es, can protect against ischemic neuronal injury by enhancing adenosine levels and potentiating adenosine receptor-mediated effects, including attenuation of the cellular production and release of tumor necrosis factor-alpha (TNF-alpha). In rats, the phosphorylated prodrug form of NBMPR, NBMPR-phosphate, or saline was administered by intracerebroventricular injection 30 min before forebrain ischemia. Seven days following the ischemic episode, rats were killed, and neuronal damage in the CA1 region of the hippocampus was assessed. The number of pyramidal neurons was significantly (p < 0.001) greater in the NBMPR-P treatment group. A trend toward protection was still evident at 28 days postreperfusion. Adenosine increased significantly during ischemia to levels eight- to 85-fold above basal. NBMPR-P treatment did not cause statistically significant increases in ischemic adenosine levels; however, this treatment tended to increase adenosine levels in all brain regions at 7 min postreperfusion. Ischemia-induced expression of TNF-alpha was not altered by NBMPR-P treatment, and the nonselective adenosine receptor antagonist 8-(p-sulfophenyl) theophylline did not abolish the neuroprotective effects of NBMPR-P treatment. These data indicate that NBMPR can protect CA1 pyramidal neurons from ischemic death without statistically significant effects on adenosine levels or adenosine receptor-mediated inhibition of the proinflammatory cytokine TNF-alpha.

Off-resonance effects of the radiofrequency pulses used in spectral editing with double-quantum coherence transfer.

Spectral editing using gradient selected double-quantum (DQ) coherence transfer is often used for the selective observation of metabolites in vivo. In attempting to optimize the detection sensitivity of a conventional DQ spectral editing sequence, the effects of using radiofrequency (RF) pulses that are not at the resonance frequency of the observed peaks were investigated both theoretically and experimentally. The results show that spectral editing using pulses at the frequency of the observed resonance does not necessarily give the optimal detection sensitivity. At 7 T, the detection sensitivity of lactate observed using a DQ editing method can be increased by up to 30% by setting the RF pulses off resonance at the proper frequency. The results also suggest that slice selective RF pulses used in DQ spectral editing combined with PRESS localization may have slice profiles different from those when the same pulses are used for standard PRESS spatial localization.

Simultaneous spectral editing for gamma-aminobutyric acid and taurine using double quantum coherence transfer.

Conventional double quantum (DQ) editing techniques recover resonances of one metabolite at a time and are thus inefficient for monitoring metabolic changes involving several metabolites. A DQ coherence transfer double editing sequence using a dual-band DQ coherence read pulse is described here. The sequence permits simultaneous spectral editing for two metabolites with similar J coupling constants in a single scan. Simultaneous editing for taurine and gamma-aminobutyric acid (GABA) is demonstrated using solution phantoms and rat brain tissue. Selectivity of the double editing sequence for the target metabolites is as good as that achieved using conventional DQ editing which selects each metabolite individually. With experimental parameters of the double editing sequence chosen to optimize GABA editing, the sensitivity for GABA detection is the same as that with GABA editing only, while the sensitivity for taurine detection is decreased slightly compared to that with taurine editing only.

Serial magnetic resonance imaging of rat brain after induction of renal hypertension.

BACKGROUND AND PURPOSE: Hypertension is a major risk factor for ischemic and hemorrhagic stroke and may also cause more chronic and subtle brain injury. Progressive brain changes in a rat model of renal hypertension have been assessed to better understand the pathogenesis of hypertensive brain damage. METHODS: Young adult rats were made hypertensive by partial occlusion of both renal arteries. MR images of brain were obtained weekly, and histopathological outcome was assessed. A separate group of rats was used to measure brain specific gravity and Evans blue dye content as an indicator of extravasation. RESULTS: Rats developed maximal mean systolic blood pressures of 173 to >300 mm Hg, reaching a plateau in 6 to 8 weeks. Rats whose mean systolic pressure never exceeded 210 mm Hg never had brain lesions, while rats whose mean systolic pressure exceeded 276 mm Hg consistently developed brain lesions. Brain T2 values increased with increasing blood pressure. Lesions seen on MRI corresponded to those seen histologically. MRI also demonstrated transient brain expansion, probably due to diffusely increased water content, and rarely demonstrated focal cortical edema, which had no histological correlate. These transient phenomena, as well as hemorrhagic and ischemic infarcts, occurred mainly during the phase of climbing blood pressure and early stages of stable hypertension. CONCLUSIONS: Serial MRI reveals aspects of hypertensive brain disease that cannot be studied by histological examination alone. The observed phenomena are likely related to loss of autoregulation and/or blood-brain barrier integrity. Breach of blood vessel integrity is less likely once the vessels become accustomed to high pressures.

A localized double-quantum filter for in vivo detection of taurine.

Noninvasive detection of taurine, an important amino acid involved in numerous physiological processes, by in vivo (1)H magnetic resonance (MR) spectroscopy is complicated by severe overlap of the taurine resonances with those of a number of other metabolites. Unambiguous differentiation of the taurine resonances requires spectral editing. In this study, the development of a localized spectral editing technique based on double-quantum filtering optimized for in vivo detection of taurine is described. The sequence recovers the taurine signal while substantially eliminating overlapping resonances and provides excellent three-dimensional spatial localization. The performance of the sequence is demonstrated both in phantoms and in rat brain in vivo. Magn Reson Med 42:454-460, 1999.

Effect of fucoidan treatment on collagenase-induced intracerebral hemorrhage in rats.

Inflammatory cells are postulated to mediate some of the brain damage following ischemic stroke. Intracerebral hemorrhage is associated with more inflammation than ischemic stroke. We tested the sulfated polysaccharide fucoidan, which has been reported to reduce inflammatory brain damage, in a rat model of intracerebral hemorrhage induced by injection of bacterial collagenase into the caudate nucleus. Rats were treated with seven day intravenous infusion of fucoidan (30 micrograms h-1) or vehicle. The hematoma was assessed in vivo by magnetic resonance imaging. Motor behavior, passive avoidance, and skilled forelimb function were tested repeatedly for six weeks. Fucoidan-treated rats exhibited evidence of impaired blood clotting and hemodilution, had larger hematomas, and tended to have less inflammation in the vicinity of the hematoma after three days. They showed significantly more rapid improvement of motor function in the first week following hemorrhage and better memory retention in the passive avoidance test. Acute white matter edema and eventual neuronal loss in the striatum adjacent to the hematoma did not differ between the two groups. Investigation of more specific anti-inflammatory agents and hemodiluting agents are warranted in intracerebral hemorrhage.

Multiple-voxel double-quantum lactate-edited spectroscopy using two-dimensional longitudinal Hadamard encoding.

A conventional gradient-selected double-quantum lactate editing sequence was combined with fourth order two-dimensional longitudinal Hadamard encoding and slice-selective refocusing to acquire lactate-edited spectra in a 3 x 3 matrix of voxels. The performance of the sequence was verified in phantoms at 9.4 T and in focally ischemic rat brain at 7.0 T. Efficient suppression of water, lipid, and the singlet resonances of creatine, choline, and N-acetylaspartate was achieved, giving multi-voxel localized lactate-edited spectra with good signal-to-noise ratio.

A strategy to optimize the signal-to-noise ratio in one-coil arterial spin tagging perfusion imaging.

The signal-to-noise ratio of the perfusion image (SNR(perfu)) in a spin-tagging experiment is shown to depend on both the degree of spin labeling (alpha) and the signal-to-noise ratio of the proton density images (SNRimage) used to calculate the perfusion image. When a single radiofrequency (RF) coil is used for both spin tagging and magnetic resonance (MR) imaging, magnetization transfer (MT) effects decrease SNRimage, and therefore SNRperfu, by an amount that depends on the strength B1 and offset deltaomega (determined by the gradient strength G(I) applied during spin tagging) of the labeling RF pulse. It is shown that by optimizing B1 and G(I), it is possible to reduce MT effects and thus increase SNRimage, while leaving alpha unchanged. As a result, SNRperfu, will be improved. An equation for calculating perfusion under general conditions of such reduced MT effects is derived and shown to give perfusion rates that are independent of the strength and offset of the labeling RF irradiation.

Simultaneous lactate editing and observation of other metabolites using a stimulated-echo-enhanced double-quantum filter.

Conventional double-quantum editing techniques recover only one metabolite at a time, and are thus inefficient for monitoring metabolic changes involving several metabolites. In this paper, a stimulated-echo-enhanced selective double-quantum coherence transfer (STE-SelDQC) sequence is described, which allows simultaneous observation of lactate and other metabolites in a single scan while leaving fat and water signals suppressed. A frequency selective double-quantum filter designed for lactate editing suppresses fat and water resonances and a stimulated-echo window of adjustable frequency and bandwidth is incorporated into the double-quantum filter for simultaneous observation of other metabolites. The performance of the sequence is demonstrated in phantoms and rat brain tissue.

Temporal profile of magnetic resonance imaging changes following forebrain ischemia in the gerbil.

Quantitative T2 magnetic resonance (MR) imaging was used to examine gerbil brains 1, 3, 10, and 30 days after 5 min forebrain ischemia. T2 was increased in the dorsal-lateral striatum 1 and 3 days post-ischemia, and in the hippocampus 3 days post-ischemia. T2 was normal 10 days post-ischemia, and decreased in the hippocampus and dorsal-lateral striatum 30 days post-ischemia. Neuronal counts in the dorsal-lateral striatum and CA1 hippocampal region were uniformly decreased 30 days post-ischemia. The increase in T2 shortly after ischemia is attributed to brain edema localized to regions where neuronal injury developed. The late decrease in T2 may be due to decreased water in gliotic tissue, or to ferritin-positive microglia, following forebrain ischemia. Tissue atrophy at later times gave enlarged ventricles on MR images.