Comparison of Gd- and Dy-chelates for T2 contrast-enhanced imaging.
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Biomedical subjects
J Mintorovitch
Publications and source records attributed to J Mintorovitch.
Magnetic resonance imaging of brain perfusion using the nonionic contrast agents Dy-DTPA-BMA and Gd-DTPA-BMA.
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Animals↗
In vivo diffusion-perfusion magnetic resonance imaging of acute cerebral ischemia.
We compared the anatomic extent and severity of ischemic brain injury shown on diffusion-weighted magnetic resonance (MR) images, with cerebral tissue perfusion deficits demonstrated by a nonionic intravascular T2*-shortening magnetic susceptibility contrast agent used in conjunction with standard T2-weighted spin-echo and gradient-echo echo-planar images. Diffusion-weighted images displayed increased signal intensity in the vascular territory of the middle cerebral artery 25-40 min after permanent occlusion, whereas T2-weighted images without contrast were negative or equivocal for at least 2-3 h after stroke was induced. Contrast-enhanced T2-weighted and echo-planar images revealed perfusion deficits that were spatially closely related to the anatomic regions of ischemic tissue injury. These data indicate that diffusion-weighted MR images are very sensitive to early onset pathophysiologic changes induced by acute cerebral ischemia. Combined sequential diffusion-perfusion imaging enables noninvasive in vivo examination of the relationship between hypoperfusion and evolving ischemic brain injury.
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Ischemic brain damage: reduction by sodium-calcium ion channel modulator RS-87476.
A novel sodium-calcium ion channel modulator, RS-87476, reduced cerebral infarct size in cats subjected to permanent unilateral occlusion of the middle cerebral artery. Cerebral injury was assessed in vivo with a combination of magnetic resonance (MR) imaging and spectroscopy for 5-12 hours after occlusion and was compared with the area of histochemically ischemic brain tissue. Compared with infarcts in placebo-treated animals, infarcts in cats given RS-87476 were reduced by an average of 70% at the lowest dose, 75% at the intermediate dose, and 88% at the highest dose. Tissue edema, observed as areas of signal hyperintensity on diffusion- and T2-weighted spin-echo images, was confined to small regions of the parietal cortex and basal ganglia in drug-treated animals. Mean plasma levels of RS-87476 at the lowest dose were 13 ng/mL initially, falling to maintenance levels of 3-5 ng/mL; at the intermediate and highest doses, plasma levels of drug were approximately five- and 20-fold greater. The drug was only slightly hypotensive. At least part of the potent cerebroprotective effects of RS-87476 result from its ability to stabilize metabolic energy reserves, reduce lactate formation in ischemic tissues, and attenuate intracerebral edema.
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Recent advances in MR imaging/spectroscopy of cerebral ischemia.
Recent advances in high-resolution MR imaging and multinuclear spectroscopy have stimulated studies of the functional relationships between tissue hypoperfusion, cellular energy depletion, and brain edema associated with cerebral ischemia. The very slow (microns/sec) random translational motion of water protons in various brain tissues and intracranial fluid compartments can now be assessed with MR diffusion imaging. More slowly diffusing protons in ischemic tissues can be differentiated from normal parenchyma, CSF, and flowing blood, enabling the detection and localization of ischemic regions within minutes of the onset of stroke. Perfusion imaging "snapshots," obtained in as little as 25 msec with echoplanar MR methods, permit the evaluation of tissue washin/washout kinetics of contrast agents in the microvasculature, and thus the quantification of brain perfusion on a regional basis. Also, delineation of major intra- and extracranial arterial and venous structures with MR angiography, acquired with two- or three-dimensional Fourier transformation techniques, has enabled accurate noninvasive assessments of vascular occlusive disease. Finally, improvements in MR spectroscopic techniques have facilitated investigations of metabolic regulation and bioenergetics in experimental animal models of cerebral ischemia, as well as in stroke patients. Combined MR imaging and spectroscopy will likely play an important role in differentiating reversibly from irreversibly ischemic brain tissues and in the investigation of various neuroprotective pharmaceuticals.
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Ultrafast magnetic resonance imaging: diffusion and perfusion.
Echo-planar magnetic resonance imaging (MRI) can be used to measure apparent diffusion coefficients noninvasively in vivo, with scan times of 150 milliseconds or less, and to assess early ischemic effects in the feline experimental model, which has an occluded middle cerebral artery (MCA). The apparent diffusion coefficient in ischemic regions, which are identified later from vital staining, is significantly decreased from normal values within 1 hour after the MCA becomes occluded. A series of 10 echo-planar images that are progressively diffusion-weighted can be collected in 1 minute (effective TR of 6 seconds). Semilogarithmic plots of image intensity versus gradient strength factors (b values) were linear. Collecting sequential gradient echo-planar images during the passage of a bolus of contrast medium is also useful when assessing perfusion or vascular integrity before and during ischemic episodes. After intravenous injection of dysprosium-diethylene triamine penta-acetic acid-bis(methylamide), typical signal losses of 40% to 80% were observed and were dose-dependent. Areas of possible ischemia identified from diffusion-weighted images did not lose signal intensity with the use of contrast medium and were seen as regions of relative hyperintensity, clearly discernible from normally perfused tissues.
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Early detection of regional cerebral ischemia in cats: comparison of diffusion- and T2-weighted MRI and spectroscopy.
Diffusion-weighted MR images were compared with T2-weighted MR images and correlated with 1H spin-echo and 31P MR spectroscopy for 6-8 h following a unilateral middle cerebral and bilateral carotid artery occlusion in eight cats. Diffusion-weighted images using strong gradient strengths (b values of 1413 s/mm2) displayed a significant relative hyperintensity in ischemic regions as early as 45 min after onset of ischemia whereas T2-weighted spin-echo images failed to clearly demonstrate brain injury up to 2-3 h postocclusion. Signal intensity ratios (SIR) of ischemic to normal tissues were greater in the diffusion-weighted images at all times than in either TE 80 or TE 160 ms T2-weighted MR images. Diffusion- and T2-weighted SIR did not correlate for the first 1-2 h postocclusion. Good correlation was found between diffusion-weighted SIR and ischemic disturbances of energy metabolism as detected by 31P and 1H MR spectroscopy. Diffusion-weighted hyperintensity in ischemic tissues may be temperature-related, due to rapid accumulation of diffusion-restricted water in the intracellular space (cytotoxic edema) resulting from the breakdown of the transmembrane pump and/or to microscopic brain pulsations.
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Early detection of ischemic injury: comparison of spectroscopy, diffusion-, T2-, and magnetic susceptibility-weighted MRI in cats.
Within one hour following MCA-occlusion in cats, heavily diffusion-weighted spin-echo MR images exhibited a well-defined hyperintensity in the gray matter and basal ganglia of the occluded side over normal side. This hyperintensity correlated with lactate and inorganic phosphate increases in peak areas from MR surface coil spectroscopy. T2-weighted MRI showed no significant abnormality in signal intensity from the occluded hemisphere within several hours post-occlusion. Using a paramagnetic MR contrast agent, dysprosium-DTPA-BMA together with heavily T2-weighted spin-echo or with T2*-weighted echo-planar (EPI) MR imaging, perfusion deficits resulting from MCA-occlusion were detected as a relative hyperintensity of ischaemic tissues compared to normally-perfused cerebral tissues in the contralateral hemisphere. Evidence of these deficits was observed within minutes of occlusion, and spatially correlated well with the hyperintensity seen on the diffusion-weighted images. Diffusion- and susceptibility-weighted MRI was superior to conventional T2-weighted MRI in the detection of early ischaemic events. In contrast to surface coil spectroscopy, both techniques mapped regions of jeopardy throughout the brain, which later showed T2-weighted hyperintensity and lack of vital (TTC) staining.
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Diffusion-weighted MR imaging and T2-weighted MR imaging in acute cerebral ischaemia: comparison and correlation with histopathology.
Diffusion-weighted MR imaging is a new technique which measures the microscopic motion of water protons. Signal hyperintensity on diffusion-weighted images correlates closely with evidence of ischaemic damage on histopathologic sections. Following occlusion of the middle cerebral artery (MCA), diffusion-weighted images indicate the presence of early pathophysiologic changes occurring first in the basal ganglia and, subsequently, in cortical gray matter within the MCA vascular territory. Diffusion-weighted images also better define the anatomic locus of ischaemic tissue injury than T2-weighted images. Diffusion-weighted imaging thus appears to facilitate early detection and thereby possible therapeutic intervention in patients with acute stroke.
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Diffusion-weighted MR imaging of anisotropic water diffusion in cat central nervous system.
The diffusion behavior of intracranial water in the cat brain and spine was examined with the use of diffusion-weighted magnetic resonance (MR) imaging, in which the direction of the diffusion-sensitizing gradient was varied between the x, y, and z axes of the magnet. At very high diffusion-sensitizing gradient strengths, no clear evidence of anisotropic water diffusion was found in either cortical or subcortical (basal ganglia) gray matter. Signal intensities clearly dependent on orientation were observed in the cortical and deep white matter of the brain and in the white matter of the spinal cord. Greater signal attenuation (faster diffusion) was observed when the relative orientation of white matter tracts to the diffusion-sensitizing gradient was parallel as compared to that obtained with a perpendicular alignment. These effects were seen on both premortem and immediate postmortem images obtained in all axial, sagittal, and coronal views. Potential applications of this MR imaging technique included the stereospecific evaluation of white matter in the brain and spinal cord and in the characterization of demyelinating and dysmyelinating diseases.
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Diffusion-weighted MR imaging of acute stroke: correlation with T2-weighted and magnetic susceptibility-enhanced MR imaging in cats.
We evaluated the temporal and anatomic relationships between changes in diffusion-weighted MR image signal intensity, induced by unilateral occlusion of the middle cerebral artery in cats, and tissue perfusion deficits observed in the same animals on T2-weighted MR images after administration of a nonionic intravascular T2 shortening agent. Diffusion-weighted images obtained with strong diffusion-sensitizing gradient strengths (5.6 gauss/cm, corresponding to gradient attenuation factor, b, values of 1413 sec/mm2) displayed increased signal intensity in the ischemic middle cerebral artery territory less than 1 hr after occlusion, whereas T2-weighted images without contrast usually failed to detect injury for 2-3 hr after stroke. After contrast administration (0.5-1.0 mmol/kg by Dy-DTPA-BMA, IV), however, T2-weighted images revealed perfusion deficits (relative hyperintensity) within 1 hr after middle cerebral artery occlusion that corresponded closely to the anatomic regions of ischemic injury shown on diffusion-weighted MR images. Close correlations were also found between early increases in diffusion-weighted MR image signal intensity and disrupted phosphorus-31 and proton metabolite levels evaluated with surface coil MR spectroscopy, as well as with postmortem histopathology. These data indicate that diffusion-weighted MR images more accurately reflect early-onset pathophysiologic changes induced by acute cerebral ischemia than do T2-weighted spin-echo images.
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Kinetic study of the slow cyanide binding to Glycera dibranchiata monomer hemoglobin components III and IV.
Compared to other monomeric heme proteins and the heme peroxidases, the Glycera dibranchiata monomer hemoglobin components III and IV exhibit very slow cyanide binding kinetics. This is agreement with the previously reported behavior of component II. Similar to component II, components III and IV have been studied under pseudo-first-order conditions at pH 6.0, 7.0, 8.0, and 9.0 by using a 100-250-fold excess of potassium cyanide at each pH. At 20 degrees C with micromolar protein concentrations, kobs for component III varies between 7.08 x 10(-5) s-1 at pH 6.0 and 100-fold cyanide excess and 1.06 x 10(-2) s-1 at pH 9.0 and 250-fold cyanide excess. For component IV, the values are 2.03 x 10(-4) s-1 for 100-fold cyanide excess at pH 6.0 and 4.13 x 10(-2) s-1 for 250-fold cyanide excess at pH 9.0. In comparison to other heme proteins, our analysis shows that the bimolecular rate constant (klapp) is small. For example, at pH 7.0, it is 3.02 x 10(-1) M-1 s-1 for component III and 1.82 M-1 s-1 for component IV, compared to 400 M-1 s-1 for sperm whale metmyoglobin, 692 M-1 s-1 for soybean metleghemoglobin a, 111 M-1 s-1 for guinea pig methemoglobin, and 1.1 x 10(5) M-1 s-1 for cytochrome c peroxidase. Our results also show that the dissociation rates (k-lapp) are extremely slow and no larger than 10(-6) s-1.(ABSTRACT TRUNCATED AT 250 WORDS)
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The effects of high pressure upon ligated and deoxyhemoglobins and myoglobin. An optical spectroscopic study.
The effects of high pressure (0.1-3.4 gigapascal (GPa)) on the ferrous heme active sites of human adult hemoglobin, sperm whale myoglobin, and Glycera dibranchiata hemoglobin (Fraction II) were probed using resonance Raman and absorption spectroscopies. High-to-low spin transitions of the heme iron occur for hemoglobin, myoglobin, and Glycera hemoglobin at 0.35, 0.75, and 0.50 GPa, respectively, for the deoxy species. These interspecies differences result from variations in the composition of the hemepockets and/or their rigidity to pressure-induced volume changes. Heme active sites initially bound to CO or O2 exhibit distinctive behavior at high pressures. For all proteins studied, O2 apparently dissociates from the heme at only moderately high pressure, while CO remains bound to the heme moiety even at extreme pressures. The Raman spectra demonstrate the differences in the ligated and deoxy species at 3.4 GPa in the high frequency region. Discrete changes (i.e. iron spin-state transitions and dissociation of O2) occur that are commensurate with the collapse of the distal pocket, while continuous shifts in the absorption and Raman spectra are observed at pressures above those required for pocket collapse.
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Anomalously slow cyanide binding to Glycera dibranchiata monomer methemoglobin component II: implication for the equilibrium constant.
In comparison to sperm whale metmyoglobin, metleghemoglobin a, methemoglobins, and heme peroxidases, the purified Glycera dibranchiata monomer methemoglobin component II exhibits anomalously slow cyanide ligation kinetics. For the component II monomer methemoglobin this reaction has been studied under pseudo-first-order conditions at pH 6.0, 7.0, 8.0, and 9.0, employing 100-250-fold mole excesses of potassium cyanide at each pH. At 20 degrees C, with micromolar protein concentrations, kobsd varies between 9.11 x 10(-5) s-1 at pH 6.0, 100-fold KCN mole excess, and 1.12 x 10(-2) s-1 at pH 9.0, 250-fold KCN mole excess. Our analysis shows that the concentration-independent bimolecular rate constant (k1app) is small in comparison to those of the other heme proteins. For example, at pH 7.0 it is 0.491 M-1 s-1, compared to 1.1 x 10(5) M-1 s-1 for cytochrome c peroxidase; 111 M-1 s-1 for guinea pig methemoglobin; approximately 400 M-1 s-1 for sperm whale metmyoglobin; and 692 M-1 s-1 for soybean metleghemoglobin a, at the same pH and similar temperatures. Furthermore, our results show that the dissociation rate is extremely slow, with k-1app no larger than 10(-6) s-1. Separation of the bimolecular rate constant into contributions from kCN- (the rate constant for CN- binding) and from kHCN (the rate constant for HCN binding) shows that the former is approximately 90 times greater. These results indicate that cyanide ligation reactions are not instantaneous for this protein, which is important for those attempting to study the ligand-binding equilibria.(ABSTRACT TRUNCATED AT 250 WORDS)
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CD studies on the reversed heme orientation in monomeric Glycera dibranchiata hemoglobins.
Circular dichroism spectra of three monomeric components of Glycera dibranchiata hemoglobins are reported. Contrary to what is found for most hemoglobins and myoglobins, G. dibranchiata hemoglobins display largely negative dichroic spectra in the Soret region. Independent NMR measurements have shown that the same monomeric hemoglobin components contain the heme moiety predominantly (greater than 85%) oriented in a reversed way with respect to the orientation which occurs in most hemoglobins and myoglobins. On the basis of these independent NMR studies, and also of previous data on other invertebrate hemoproteins, a correlation appears evident between reversed heme orientation in hemoglobins and negative ellipticity in the Soret CD spectrum. This represents a simple tool to evaluate this aspect of heme asymmetric environment.
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The structural bases for the unique ligand binding properties of Glycera dibranchiata hemoglobins. A resonance Raman study.
The hemoglobin of the marine annelid Glycera dibranchiata possesses several unique features: the hemoglobin consists of multiple monomeric and polymeric components, quaternary structure is lacking, the distal histidine is replaced by leucine in at least one monomeric constituent, and 4) the protein exhibits extremely rapid ligand binding kinetics. The effect of these structural modifications on the ligand binding process has been evaluated using resonance Raman spectroscopy to examine the vibrational modes of the porphyrin macrocycle in deoxy and carbonmonoxy equilibrium species of hemoglobin G. dibranchiata in both the unseparated monomeric and polymeric forms and in a single monomeric component designated Fraction II. Significant differences relative to hemoglobin were found in porphyrin pi electron density, vinyl environment, low frequency vibrational modes, and, in particular, the Fe-proximal histidine stretching mode. Spectra of the deoxy heme transients generated within 10 ns of ligand photolysis have also been examined. These clearly indicate large differences in the heme pocket dynamics subsequent to CO photolysis in G. dibranchiata hemoglobins relative to other hemoglobins. The significance of these results in terms of the kinetics and thermodynamics of ligand binding is discussed.
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Cerebrovascular transit characteristics of DyDTPA-BMA and GdDTPA-BMA on normal and ischemic cat brain.
PURPOSE: To compare the efficacy of two nonionic T2*-shortening contrast agents, DyDTPA-BMA dysprodiamide injection and GdDTPA-BMA gadodiamide injection, as perfusion-sensitive MR imaging agents in normal and acutely ischemic brain. METHODS: The magnetic susceptibility effects of intravenous injections of 0.10-0.50 mmol/kg of each contrast agent were quantified on T2-weighted spin-echo images of cat brain before and after unilateral occlusion of the middle cerebral artery by measuring signal intensity changes in the same regions-of-interest in parietal cortex. RESULTS: In normal brain, DyDTPA-BMA produced a significantly greater loss of signal intensity than equimolar doses of GdDTPA-BMA. The magnitude of the signal intensity attenuation was dosage-dependent and proportional to the square of the magnetic moments of the two contrast agents. Restoration of baseline image signal intensity was observed within 30 min after each injection. However, injection of GdDTPA-BMA also produced a delayed, persistent hyperintensity on T2-weighted images, presumably due to its underlying T1-shortening effect. Following unilateral occlusion of the middle cerebral artery, unenhanced T2-weighted images failed to show evidence of cerebral injury for 1.5-3 hours. Administration of 0.10-1.0 mmol/kg DyDTPA-BMA shortened the time for detection of perfusion deficits (residual hyperintensity) in 22 of 36 (61%) treated cats, often to within 30 min after arterial occlusion. DyDTPA-BMA enhancement also improved lesion conspicuity in 26 of 36 (72%) cases, and disclosed very small infarcts that were not visible on T2-weighted precontrast images. Perfusion deficits in areas of partial ischemia were seen more clearly on DyDTPA-BMA-enhanced images than after equimolar injections of GdDTPA-BMA. CONCLUSIONS: Magnetic susceptibility contrast-enhanced MR imaging enables detection of perfusion deficits associated with acute cerebral ischemia well in advance of conventional T2-weighted spin-echo MR imaging without contrast. DyDTPA-BMA appears to delineate regions of ischemic damage better than GdDTPA-BMA.
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