Hyperpolarized and Inert Gas MRI. From Technology to Application in Research and Medicine


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From Theoretical Models to Experimental Measurements

It is preferred, however, that a cold trap, such as is known in the art, be used. The delivery of the noble gas to a sample may be performed as single or multiple bolus delivery. Such delivery would ordinarily be suited to the study of systems in which observations of the change in noble gas distribution is important. Such systems would include, inter alia, human or animal subjects in which an anatomical or physiological event or events are being examined as a function of time.

Alternatively, the delivery of the noble gas to a sample may be performed as a continuous or quasi-continuous delivery. Such delivery would ordinarily be desired when steady state analyses of samples are desired. For example, high resolution imaging of human or animal organ systems would be possible by sequential imaging of steady state Xenon concentrations by data processing, e. For example, hyperpolarized Xenon could be introduced in the gastro-intestinal tract of a subject to inflate the regions therein and to provide contrast enhancement when digital subtraction of signals is performed.

Comparative data have been obtained which illustrate the NMR behavior of Xe in various environments. For example, various groups have determined chemical shift and relaxation rates T 1 and T 2 for Xe in environments such as n-octanol, benzene, water and myoglobin.

See References 2, Octanol represents a relatively non-polar lipid-like environment resembling the interior of the cell membrane, water models aqueous regions, and the myoglobin solution represents a protein to which Xenon is known to bind. The measured range of resonance frequencies for Xenon extends approximately ppm over the gas and condensed phase. Although the range of chemical shifts observed in these model biological systems is not as large as that in other solvents, it is large compared to the relevant 19 F brain resonance values that have been reported. Moreover, the huge range of T 1 values is extraordinary.

Table III lists some reported values of T 1 and T 2 for Xe in octanol, water and aqueous Fe III metmyoglobin Reference 54 ; models representing two major cell compartments, lipid membrane and cytosol.

The values for T 1 in octanol, 80 s, and water, s, provide an indication of the extraordinarily long lifetimes of Xe polarization anoxic tissue with no other relaxers. In other biological environments, longer T 1 values are possible. The extremely short T 1 and T 2 values found for the protein solution certainly occur because Xenon binds very near the paramagnetic center of metmyoglobin. Measurements of T 1 and T 2 for Xe are difficult to obtain, hence scarce.

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US6123919A - Magnetic resonance imaging using hyperpolarized noble gases - Google Patents

The values quoted here represent a significant fraction of the known list. The difficulties are obvious: typically, longitudinal relaxation times are long; low signal strength requires signal averaging of many free induction decay FID traces, hence very long overall accumulation times. Seeking a system that would be tolerably stable for the necessary time interval, capable of being sealed with Xenon at atm, but close enough to functioning brain cells, the behavior of Xenon in a synaptosome suspension has been studied.

Synaptosomes are presynaptic nerve terminals sheared away from their attachments to form resealed subcellular pseudocells that retain the morphology and chemical composition of the terminal nerve cell region, and much of the membrane functionality. Synaptosomes are rich in postsynaptic adhesions and constitute a source for postsynaptic membranes, synaptosomal mitochondria, transmitter receptors, and cleft material. This spectrum is resolution-enhanced with Gaussian broadening of 0.

Two peaks can be seen; a broad resonance of about 3. The narrow peak appeared 0. Although collected using a simple one-pulse sequence, the spectrum required 27 hours of signal averaging to obtain the degree of signal strength and resolution shown. An alternative model for investigating Xe behavior in brain tissue has also been tested.

See Reference This spectrum also shows two resolved peaks; indicating that slow-exchange compartmentalization of Xe in complex biological systems can also be observed. The decrease in high-field signal aqueous Xe as compared to the synaptosomal spectrum FIG. The spectrum of FIG. The behavior of Xe in brain tissue has been studied by investigating whether any signal could be obtained from Xe in whole rat brains.

The two resolved peaks provide further evidence that Xe is slow-exchange compartmentalized in complex biological systems. The spectrum required 8 hours of data accumulation, again-illustrating the difficulty of obtaining NMR data from Xe in biological systems. The solubility of Xenon and also of dioxygen in water is low. Due to the low sensitivity of the Xe signal, the time required for determining the relaxivity of O 2 toward Xe with a series of T 1 determinations over a range of O 2 concentrations in water would be prohibitively long. The relaxivity of O 2 toward Xe has been measured in only one liquid, i.

The observed relaxivity, 0. This translates into a T 1 value of 18 s in air-saturated lipid, and 80 s in anaerobic lipid, in the absence of other relaxers. This is the first reported value for the O 2 relaxivity toward Xe in a condensed phase. T 2 values over these O 2 concentrations have been determined to range from 0. These results indicate that the range of T 1 to be expected in tissue in vivo is about s. In fact, given the relative inefficiency of the known non-paramagnetic relaxation mechanisms, it is suspected that T 1 in many tissues will not fall below seconds or even tens of seconds.

These results are of critical importance to physiological studies using Xe magnetic resonance spectroscopy. However, since 12 hours were required to obtain this data set, the result serves only to estimate what the normal physiological T 1 might be in vivo. Although this result, obtained over a 12 hr period using Boltzmann Xe , might not be representative of physiological blood, the changes likely to occur in blood maintained at room temperature for long periods, e.

One can also estimate T 1 values for other model systems. T 1 for Xe in octanol, a classic membrane phase model, is 80 s.

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Since membrane bilayers sequester both Xe and O 2 , it should be possible to use the values for Xenon and Oxygen distribution ratios, Reference 45 , between octanol and water of and , respectively, and of the O 2 relaxivity in octanol of 0. While the actual values of T 1 in each tissue must be, and remain to be, determined, it is expected that the minimum value will fall above 15 s, a duration sufficient to enable significant accumulation of polarized Xe in major tissues.

The unusual and extraordinary properties of hyperpolarized noble gases permit imaging of a wide variety of organs, body systems, and anatomical structures. Such structures can be imaged in live or deceased subjects, depending on application, and such subjects can include human as well as animal subjects. For example, hyperpolarized Xenon will have particular clinical importance in providing nuclear magnetic resonance imaging of neural tissue diseases, vascular plaques, compromised blood flow, tumors, as well as functional imaging of the brain's response to sensory stimuli.

The properties of other noble gases will render them useful in a variety of is other situations. For example, it is expected that because of its low solubility, 3 He will be of major clinical importance in imaging anatomical spaces such as lung or other artificially inflated organs. The differential solubility of Xenon and other lipid soluble, hyperpolarizable noble gas isotopes would permit noble gas NMR differentiation between white and gray matter in brain tissue, while lipid membranes are essentially invisible to 1 H 2 O MRI.

Hyperpolarized and Inert Gas MRI: From Technology to Application in R…

For example, with respect to neural tissue disease, in white matter regions of the lower medulla and the spinal cord 1 H 2 O MRI contrast is poor, while the high lipid solubility of Xenon and other noble gas anesthetics will permit imaging of hyperpolarized isotopes. Such imaging would have diagnostic importance for patients suffering from nerve tissue demyelination.

Hyperpolarized noble gas MRI would be of use for imaging of subdural hematomas as well as cystic and necrotic changes. Indications of low noble gas uptake in avascular regions would be valuable in demonstrating isodense fluid collections. In cases of multiple sclerosis, 1 H 2 O MRI often cannot provide useful images of plaques, while differential noble gas uptake high in normal tissue vs.

Major breakthrough in new MRI scan technology for lung disease

Similarly, in cerebral vascular and peripheral blood vessel plaques, the plaques have little or no noble gas uptake and would appear dark in a noble gas image. Images of Xenon and other noble gas anesthetics would also indicate cerebral, coronary and peripheral vessel defects; providing obvious indications of blood vessel constrictions and aneurysms.

In particular, measurements of regional cerebral blood flow would be possible with greater exactness than is possible with other techniques. Also, study of the effects of spasms on blood flow in cases of subarachnoid hemorrhage would be rendered possible. Functional study of brain tissue is also expected to be dramatically enhanced by the imaging of hyperpolarized noble gas anesthetics, especially Xenon, according to the invention. For example, changes in local blood flow caused by visual, tactile, and other stimuli should produce dramatic fluctuations in Xe signal intensity.

In addition, the elucidation of the precise relationships between neurological changes and psychological states has been a major goal of neurobiologists. Hyperpolarized Xenon MRI, with its high sensitivity, as exploited through fast electronics, has the potential to make huge contributions to this area. Disease states such as epilepsy, schizophrenia, depression and bipolar illness can be studied.

Clearly, hyperpolarized noble gas MRI has essentially unlimited potential application in medical settings. Hyperpolarized noble gas MRI could displace or supplement conventional MRI, and even the ubiquitous but intrusive X-ray CT scan, in at least several large areas: 1 the lung, heart, and cardiovascular systems; 2 the brain, especially since brain membrane lipids are invisible using current techniques; 3 brain function, since the Xe signal will respond directly and strongly to metabolic changes in neural tissue.

The near million-fold enhancement in sensitivity to noble gases enabled by hyperpolarization should result in temporal and spatial resolution in imaging superior to that achievable with 1 H 2 O. In addition, the solubility of, for example, Xenon in lipids should permit imaging of organs that currently require far more intrusive techniques such as X-ray computerized tomography scanning.

The following non-limiting Examples are intended to further illustrate the present invention. In the Examples provided below, the experimental conditions were as follows unless otherwise noted: magnetic resonance spectra were obtained using a Bruker MSL spectrometer equipped with a 9. The spectrometer was not field frequency locked during the image acquisitions. Xenon-Oxygen and Xenon-Oxygen-octanol "Boltzmann" imaging phantoms were prepared by standard quantitative high-vacuum gas-transfer techniques.

This sampling-pulse technique was originally introduced by Look et al. This image may be compared to those images in FIG. Note that, as shown in FIG. Images of hyperpolarized Xe in glass sphere phantoms were obtained as follows.

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Before filling, the cells were coated with a siliconizing agent Surfasil obtained from Pierce, of Rockford, Ill. The silicone coating apparently reduces relaxation of Xe on the walls of the glass sphere, permitting creation of larger polarizations. The spheres were then filled with Torr Xe, 75 Torr N 2 and a few milligrams of Rubidium metal. Optical polarization was performed generally in accordance with techniques known in the art, in particular the methods of Cates et al. The laser illumination of the cells was performed in the bore of the 9. After min. The laser-polarization was performed within the bore of the 9.

The other slices were obtained from sections closer to the center of the spherical phantom and are more homogeneous and uniformly bright.


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Nuclear magnetic resonance images of mouse lungs were obtained using hyperpolarized Xe according to the following method. In order to deliver a quantity of hyperpolarized Xe to a biological specimen, several obstacles must be overcome. To date, Xe has only been successfully hyperpolarized in very pristine environments such as sealed glass cells.


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Such purity is essential because any paramagnetic impurities will greatly reduce the longitudinal relaxation time T 1 of the gas and thus lower the achievable polarizations.

Hyperpolarized and Inert Gas MRI. From Technology to Application in Research and Medicine Hyperpolarized and Inert Gas MRI. From Technology to Application in Research and Medicine
Hyperpolarized and Inert Gas MRI. From Technology to Application in Research and Medicine Hyperpolarized and Inert Gas MRI. From Technology to Application in Research and Medicine
Hyperpolarized and Inert Gas MRI. From Technology to Application in Research and Medicine Hyperpolarized and Inert Gas MRI. From Technology to Application in Research and Medicine
Hyperpolarized and Inert Gas MRI. From Technology to Application in Research and Medicine Hyperpolarized and Inert Gas MRI. From Technology to Application in Research and Medicine
Hyperpolarized and Inert Gas MRI. From Technology to Application in Research and Medicine Hyperpolarized and Inert Gas MRI. From Technology to Application in Research and Medicine
Hyperpolarized and Inert Gas MRI. From Technology to Application in Research and Medicine Hyperpolarized and Inert Gas MRI. From Technology to Application in Research and Medicine
Hyperpolarized and Inert Gas MRI. From Technology to Application in Research and Medicine Hyperpolarized and Inert Gas MRI. From Technology to Application in Research and Medicine

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