Patent Application
20190107593
The present invention relates generally to medical imaging. More particularly, the present invention relates to a method of magnetic resonance imaging.
Magnetic resonance imaging (MRI) has long been used to create detailed internal images for use in medical diagnostics and treatment as well as studies of the brain and body. In MRI, a powerful magnetic field is used to align the magnetization of atomic nuclei in the body, and radio frequency is used to alter the alignment of the magnetization. The nuclei then produce a rotating magnetic field that is detectable by an MRI scanner and recordable to create images of the scanned area of the body. Over the years, various techniques have been developed to perform MRI scans that produce images for specialized diagnostics.
One type of MRI scan is known as magnetization transfer contrast (MTC) MRI. With regards to imaging technology, MTC refers to the transfer of magnetization from protons in semi-solid and solid-like motional environments to the water protons. In MRI one can approximately distinguish two broad classes of molecules based on their motional and relaxation properties, mobile and semi-solid/solid molecules. Mobile molecules have a faster average rotational frequency and therefore their protons experience reduced coupling to surrounding protons and thus reduced transverse relaxation (extreme narrowing regime). Because of this, most protons in mobile molecules have a narrow Lorentzian resonance lineshape visible in the normal proton MR spectrum in a bandwidth of about 10 ppm around the water proton resonance frequency. This phenomenon is known as “motional averaging” or extreme narrowing and is characteristic of protons in mobile molecules. In contrast, semi-solid and solid molecules have very slow rotational frequency and protons in such an environment are relaxed strongly by dipolar coupling with neighboring protons and though chemical shielding anisotropy leading to resonances of tens of kHz (hundreds or even thousands of ppm) wide and not visible in the normal proton spectrum.
Exchange mechanisms, such as through-space dipolar coupling or proton chemical exchange (physical exchange of protons such as OH, NH or SH protons) between molecules allow the protons in both mobile and semi-solid/solid macromolecules to interact with the bulk (solvent) media and establish a dynamic equilibrium.
The MTC methodology detects magnetization transfer from the MR-invisible semi-solid/solid protons to the bulk water via these processes. While there is no measurable signal from the semi-solid spins due to the very short T2 (order of microseconds), the longitudinal magnetization is better preserved and after excitation of the proton spin system recovery via T1 relaxation is relatively slow. The longitudinal magnetization of the semi-solid/solid spins can be selectively altered and transferred between the protons in the semi-solid/solid, and, in turn, this alteration can be measured in the spins of the bulk media, due to the exchange processes. The conventional MTC sequence applies an RF saturation (either continuous or pulsed) at a frequency that is off-resonance for the narrow line of bulk water but still on resonance for the bound protons with a spectral linewidth in the range of tens to hundreds of kHz. This causes saturation of the bound spins and transfer of this saturation within this semi-solid/solid environment via fast spin-diffusion, an intramolecular through-space dipolar coupling phenomenon. This saturation can subsequently exchange into the bulk water either through (i) through-space dipolar coupling with bound water or (ii) physical exchange of protons in OH, NH, NH2 and SH groups, resulting in a loss of longitudinal magnetization and hence signal decrease in the bulk water. Because of the slow motional state of the water bound to the semi-solid, it is generally assumed that mechanism (i) is a main contributor. The magnetization transfer provides an indirect measure of semisolid/solid macromolecular content in tissue. Implementation of MTC therefore involves choosing suitable frequency offsets and pulse shapes to saturate the semi-solid/solid spins sufficiently specific, i.e. without affecting mobile systems in the normal proton spectrum.
The spin-diffusion in semi-solid/solid systems is one example of intramolecular nuclear overhauser enhancement (NOE) effects. Intramolecular NOEs are a type of through-space dipolar, cross-relaxation that can occur between nuclei that are in spatial proximity. Their magnitude and detectability depend on the distance between the nuclei (effect proportional to 1/r6, with r being the distance between protons) as well as on the molecular tumbling rate (motional range). They can occur between nuclei with a magnetic moment (e.g. 1H, 13C, 31P, 15N, 19F, etc.) both homonuclear, e.g. 1H-1H and heteronuclear, e.g. 1H-13C. They happen extremely fast in semi-solid/solid systems and slower in mobile macromolecules.
NOE effects have been studied in high-resolution NMR spectroscopy in solution (in vitro) for several decades and are used there to assess molecular structure, molecular dynamics and molecular binding. The 2002 Nobel Prize in Chemistry was given to Kurt Wüthrich for the use of intramolecular NOEs in multidimensional spectroscopy for the determination of macromolecular structure. Fast intramolecular NOE effects (also called spin diffusion) occur within semi-solids or solid components of tissue and have been used in conventional magnetization transfer contrast (MTC). In MTC such solid and/or semi-solid compounds can be excited in a resonance range separate from solvent water because of a very short T2 on the order of microseconds. In MTC, after this off resonance excitation, the magnetization is transferred to the water in large part using through-space intermolecular transfer to bound water.
While conventional methods of MTC observation of NOE effects are quite useful, these known methods are used only to study semi-solid and/or solid compounds or tissue constituents that have characteristically short T2s in the microsecond range. It would therefore be advantageous to have a method for water-based observation of NOE effects between non-exchangeable protons with a long T2 in mobile solutes, including for macromolecules such as proteins and peptides as well as for small molecules.
It is also well known from basic NMR that NOE (dipolar cross relaxation) and chemical exchange (CE) are possible types of magnetization transfer (MT) pathways that may contribute to saturation transfer experiments. Their pathways are active together in most MT experiments and difficult to separate completely. The relative contributions of these pathways may vary with the type of excitation scheme used and depend on the molecular mobility and conformation, which will affect dipolar transfer efficiency and water accessibility, respectively.
It would therefore be advantageous to provide a method of MRI that images exchange relayed intramolecular nuclear overhauser enhancement effects in mobile solutes generated by the saturation of non-exchangeable protons, the transfer of the signal to exchangeable protons, and subsequent transfer of the signal to water, such that the contrast is visible on the water, while the effects of conventional MTC are very small.
The foregoing needs are met, to a great extent, by the present invention, wherein in one aspect, a method for obtaining a magnetic resonance imaging (MRI) image, includes performing a magnetic labeling MRI experiment on non-exchangeable protons of molecules with resonances of finite linewidth in the NMR proton spectrum. The method also includes waiting for intramolecular nuclear overhauser enhancement (NOE) effects to occur between the non-exchangeable protons types and non-exchangeable and exchangeable protons in the same molecule during a magnetic steady state and monitoring a reduction in a water signal due to a transfer of NOE labels to the water signal in a manner relayed through the exchangeable protons. Additionally, the method can include performing analysis to produce an image of the subject.
In accordance with another aspect of the present invention the non-exchangeable protons can take the form of one or more of the group of aliphatic, olefinic, and aromatic protons. These non-exchangeable protons can be endogenous or exogenous molecules and have a transverse relaxation time T2 in the millisecond range due to the mobile properties of the molecule, which makes them resonate in the boundaries of the normal proton spectrum about ±10 ppm around the water proton resonance. The step of performing magnetic labeling can also include selectively irradiating and saturating one or more of the non-exchangeable protons for a particular compound over a predetermined frequency range, as well as, selectively exciting one or more protons of the non-exchangeable protons for a particular compound over the predetermined frequency range. Selectively exciting the protons can further include pulsed radiofrequency (RF) inversion using one or more RF pulses, and selectively irradiating and saturating further includes inducing a magnetic steady state such that intramolecular NOEs occur in mobile solute molecules.
In accordance with another aspect of the present invention, the endogenous molecules can include one or more of the group of: tissue molecules containing non-exchangeable aliphatic, olefinic or aromatic protons as well as exchangeable protons, and wherein the endogenous molecules are in the appropriate motional range to allow intramolecular NOEs to occur between non-exchangeable protons and between non-exchangeable and exchangeable protons during the steady state. Tissue molecules can include at least one of the group of proteins, peptides, sugars, metabolites. The contrast agent can include at least one of the group of proteins, peptides, sugars, small organic compounds, small inorganic compounds, organic polymers, inorganic polymers, inorganic complexes, and other mobile species that can be administered in vivo. Notice that when inorganic complexes contain paramagnetic shift metals, the range of the mobile proton resonances may be outside of the normal proton spectrum of 0-10 ppm and cover a large range over which we can excite the non-exchangeable protons and induce NOEs.
In accordance with still another aspect of the present invention, the contrast agent can be configured to be in a predetermined mobility range to display exchange-relayed NOE effects for one of the proton ensembles in vivo or in vitro. Mobility of the contrast agent can be reduced by binding the agent or entering a more viscous environment, which may allow our method to be used to study molecular binding or binding-based reactions in vivo or in vitro.
In accordance with yet another aspect of the present invention, the method can further include using a pulsed steady state MRI sequence containing a short saturation labeling RF pulse followed by a small flip angle excitation pulse and brief spatial encoding of one or more spatial frequencies to selectively irradiate and saturate one or more protons and waiting for NOEs to occur is accomplished frequencies. The method can also further include choosing the pulse sequence parameters to sufficiently reduce the simultaneously occurring effects of MTC contrast to allow visualization of the exchange-relayed NOE contrast. Additionally the method can include monitoring of the water reduction over a predetermined range of frequencies to allow depiction of a direct water saturation. Further, the monitoring of the water reduction can be used to allow a determination of the water frequency shifts on a voxel by voxel basis.
In accordance with another aspect of the present invention, one possible step of performing analysis further includes fitting of a frequency-dependent direct water saturation with a Lorentzian lineshape and subtracting this from the frequency dependent total saturation spectrum to determine an exchange-relayed NOE effect. The step of performing analysis further includes monitoring a water saturation at an appropriate frequency for the protons. Additionally, multiple contrast agents with different types of protons, such as aliphatic, olefinic, and aromatic protons, or single agents containing such multiple proton types can be used to have multiple proton frequencies. An exchange-relayed NOE water signal intensity can be used to monitor pH based on changes in exchange rate with pH, and an effect on the water signal of the contrast agents to monitor concentration of the agent. In accordance with yet another aspect of the present invention, an image produced as a result of the method can take the form of a one-dimensional, two-dimensional or three-dimensional image. Alternatively a spectrum can be acquired without spatial encoding.
In accordance with still another aspect of the present invention, a method for obtaining a magnetic resonance image (MRI) of a subject can include performing a magnetic labeling MRI experiment on non-exchangeable magnetic nuclei with resonances of a finite line width and waiting for an intramolecular nuclear overhauser enhancement (NOE) effect to occur between the non-exchangeable magnetic nuclei and the non-exchangeable and exchangeable magnetic nuclei in the same molecule during a magnetic steady state. The method of labeling can include a single RF pulse or a combination of RF pulses selectively exciting the mentioned non-exchangeable protons and generating non-equilibrium longitudinal magnetization. The method also includes monitoring a reduction in the water signal or a modulation in the water signal due to the transfer of NOE labels to the water signal in an exchange-relayed manner. Additionally, the method includes acquiring the data to produce an image or spectrum of the subject and subsequently analyzing this data.
In accordance with an aspect of the present invention, the magnetic nuclei can take the form of at least one of the group of 1H, 15N, 13C, 31P, 17O, 23Na. The magnetic nuclei can further include any magnetic nuclei identified in the periodic table.
In accordance with yet another aspect of the present invention, a system for providing a magnetic resonance image of a subject in an examination region during a magnetic resonance imaging session includes a magnet configured to generate a magnetic field in the examination region and a gradient coil that superimposes a magnetic field gradient on the magnetic field. The system also includes an RF coil configured to introduce RF pulses to the examination region to magnetically label non-exchangeable magnetic nuclei with resonances of a finite line width in the sample such that an intramolecular nuclear overhauser enhancement (NOE) effect occurs between the non-exchangeable magnetic nuclei and non-exchangeable and exchangeable magnetic nuclei in the same molecule during a magnetic steady state followed by a magnetization transfer through chemical exchange. Additionally, the system includes a scan controller which controls the gradient coil and the RF coil to perform the magnetic resonance imaging session and a receiver configured to receive magnetic resonance signals during the magnetic resonance imaging session. A processor configured to receive data from the receiver is also used, such that the processor is further programmed to convert the magnetic resonance signals into the magnetic resonance image.
The accompanying drawings provide visual representations which will be used to more fully describe the representative embodiments disclosed herein and can be used by those skilled in the art to better understand them and their inherent advantages. In these drawings, like reference numerals identify corresponding elements and:
The presently disclosed subject matter now will be described more fully hereinafter with reference to the accompanying Drawings, in which some, but not all embodiments of the inventions are shown. Like numbers refer to like elements throughout. The presently disclosed subject matter may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. Indeed, many modifications and other embodiments of the presently disclosed subject matter set forth herein will come to mind to one skilled in the art to which the presently disclosed subject matter pertains having the benefit of the teachings presented in the foregoing descriptions and the associated Drawings. Therefore, it is to be understood that the presently disclosed subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims.
An embodiment in accordance with the present invention provides a method for imaging exchange-relayed intramolecular Nuclear Overhauser Enhancement (NOE) effects with MRI in mobile solutes. In the method, non-exchangeable protons with resonances of a finite linewidth in the NMR proton spectrum are magnetically labeled within a subject. Intramolecular NOE effects can then transfer the label between the non-exchangeable protons and non-exchangeable and exchangeable protons in the same molecule during a magnetic steady state. The water signal is monitored to observe a reduction or modulation in the water signal due to the transfer of NOE labels to the water signal in a manner relayed through the exchangeable protons. Analysis can be performed to produce an image or a spectrum of the subject.
More particularly, the non-exchangeable protons can take the form of aliphatic (alkyl), olefinic (alkene) or aromatic protons with resonances of finite linewidth in the NMR proton spectrum. Alternately, the protons can include any non-exchangeable proton with a sufficiently long transverse relaxation time, T2, on the order of milliseconds in mobile molecules. These protons can be endogenous compounds in the cell, interstitial space or body fluids such as proteins, peptides, carbohydrates, or smaller metabolites. Additionally, exogenously applied molecules can be used such as diamagnetic or paramagnetic contrast agents taken up in the body. Preferably, the labeled protons will not include the semisolid or solid compounds or tissue constituents studied with conventional magnetization transfer contrast (MTC) that have characteristically short T2s in the microsecond range and broadened resonances in the proton spectrum that extend well beyond the usual proton spectral range of about 0-12 ppm, with water being around 4.7 ppm. Notice that paramagnetic solutes may have shifted non-exchangeable resonances of finite linewidth and that the magnetic labeling of such resonances is also included in the present invention.
The intramolecular NOEs sought in the present method can be detected for molecules in solution through magnetic labeling (saturation or excitation) of non-exchangeable protons with T2s in the millisecond range and resonances of finite linewidth in a range of about 10 ppm around the water resonance for diamagnetic compounds and outside this range for paramagnetic compounds. The magnetic labeling is then transferred to the water signal for imaging through exchange-relayed NOE transfer. Generally, in conventional methods for chemical exchange saturation transfer (CEST) MRI, exchangeable protons are directly saturated using radiofrequency and transferred to water immediately through physical (chemical) exchange without through-space dipolar transfer. In MTC experiments, protons with very short T2s (low microsecond range) are excited and NOEs are transferred mostly directly through space to bound water molecules (intermolecular NOE transfer). In contrast, the pulse sequence of the present invention is focused on mobile species where intermolecular NOEs are negligibly small compared to exchange-relayed intramolecular NOE effects. In addition, the pulse sequence is designed to also minimize NOEs between solid and semi-solid tissue components and water. While CEST effects are also retained, these effects occur in a different frequency range in the MR spectrum. Therefore, their interference is not an issue.
As noted above, in the performance of this method 10, illustrated in
An exogenous molecule, used in the method 10, illustrated in
Step 14 of the method 10, illustrated in
As illustrated in
Step 18 of the method 10, illustrated in
With respect to the details regarding the protons and contrast agents that can be used, the discussion above applies to this method 20, as well. The discussion of the method of analysis discussed above with respect to method 10's step 18, also applies to method steps 22-28, as well as the discussion of the method of analysis below. However these methods of analysis are not meant to be limiting, and any analysis method known to one of ordinary skill in the art could be used to analyze and convert the data from the MRI experiment described in method 20 into images.
A gradient coil 46 is also illustrated in
Data received by the scanner system can then be transmitted to the processor 54 also illustrated in
In order to get a better understanding of the competing MT processes in mobile macromolecules (i.e. as reflected in T2 relaxation times that cause finite linewidths at the appropriate NMR frequency) in solution, it is possible to study the inverse effect through direct magnetic labeling of water molecules using saturation or inversion and to measure the effect on the proton spectrum as a function of time. This so-called Water-Exchange filter (WEX) experiment designed by us has been done for macromolecules in solution as well as on perfused cancer cells and in vivo in the brain.
In addition to exchange-relayed intramolecular NOEs, in which inversion is transferred from water to the molecule through exchangeable groups (mainly OH and NH2, but also NH) and subsequently to the backbone aliphatic protons, a second cross-relaxation effect (direct intramolecular NOE) occurs because of simultaneous inversion of the C(α)-H protons that resonate close to the water frequency. The exchange-relayed NOEs and intramolecular NOEs build up slower than the direct proton chemical exchange, which is illustrated for perfused cancer cells in
When performing MR saturation experiments as a function of frequency, multiple effects occur, which can be visualized in a so-called Z-spectrum, in which the water saturation is plotted as a ratio for remaining signal after saturation (Ssat) with respect to the full water signal without saturation (S0). The principle of this approach is illustrated in
If the solute protons have a sufficiently fast exchange rate (ms range) and the saturation time (tsat) is sufficiently long (s range), prolonged irradiation leads to substantial enhancement of this saturation effect, which eventually becomes visible on the water signal, as illustrated in
This process is characterized by subtracting right (−Δω) and left (Δω) signal intensity ratios through:
MTR
asym(Δω)=MTR(Δω)−MTR(−Δω)=Ssat(−Δω)/S0−Ssat(Δω)/S0 [1]
in which Δω is the frequency difference with water. Similar to MTC imaging, it has to be realized that this type of quantification is often difficult to reproduce between laboratories because, unless saturation efficiency is 100%, the effect depends on the radiofrequency power level (B1). This can be somewhat ameliorated by taking left/right ratios of the signal attenuation instead of differences, but doing this complicates quantification in terms of exchange rates and concentrations. Asymmetry analysis also is based on an inherent assumption of symmetry of non-CEST contributions around the water signal, which often is not true, especially in vivo but also in vitro.
CEST effects are generally clearly asymmetric with respect to the water frequency, while MT effects look symmetric, as illustrated in
If such NOEs occur, they will reduce the apparent CEST effect measured by asymmetry analysis. To avoid such complications and to allow the separate assessment of exchange-relayed intramolecular NOE and CEST effects in vivo with minimal interference of MTC effects, a pulse sequence was designed that accomplishes the build-up of a magnetization steady state in which the effects of competing solid-like magnetization transfer effects are very small so that the exchange-relayed effects of non-exchangeable protons as well as CEST effects can be directly visualized. It also requires a procedure for analyzing saturation spectra without the need for using so-called asymmetry analyses that is current state of the art for assessing chemical exchange saturation transfer effect in MRI. This analysis includes a fitting of the direct water saturation using so-called Lorentzian Difference Analysis (LDA).
This LDA consists of selecting a set of points in a narrow range around the water line as well as several points further downfield and/or upheld (about 9-10 ppm or more from the water resonance) and to fit a Lorentzian lineshape. The Lorentzian curve can be used to shift the acquired data to correct for B0 inhomogeneity and to determine CEST/APT and exchange-relayed NOE effects. The CEST/APT and exchange-relayed NOE signals can be quantified without the need to use the up-field side as a control.
Note that the build-up of saturation and consecutive NOEs and exchange transfer depends on the RF power and, as shown in
This method can be applied to a number of clinical and diagnostic applications. One of these is to assess the effects of pH during ischemia or other pathologies in which pH is affected, as reflected in a change in the rate of the exchange-relayed process that is used to visualize the intramolecular NOE effects. Another is to visualize changes in concentration in any of the endogenous compounds that contribute to such NOE effects in pathologies such as cancer, neurodegeneration (Alzheimer's disease, Huntington's disease, multiple sclerosis, etc.), diabetes, inflammation, etc. The methodology can detect changes in tissue properties for both endogenous and exogenous compounds, including but not limited to pH changes, concentration changes, and changes in mobility (e.g. upon binding). Applications encompass clinical areas related to disease detection, staging, and monitoring of treatment as well as detection of molecular markers and specific cells (e.g. stem cells) for molecular and cellular imaging. These examples are not meant to be limiting and this method could be applied to any number of diagnostic areas.
The many features and advantages of the invention are apparent from the detailed specification, and thus, it is intended by the appended claims to cover all such features and advantages of the invention, which fall within the true spirit and scope of the invention. Further, since numerous modifications and variations will readily occur to those skilled in the art, it is not desired to limit the invention to the exact construction and operation illustrated and described, and accordingly, all suitable modifications and equivalents may be resorted to, falling within the scope of the invention.
Although the present invention has been described in connection with preferred embodiments thereof, it will be appreciated by those skilled in the art that additions, deletions, modifications, and substitutions not specifically described may be made without departing from the spirit and scope of the invention as defined in the appended claims.
This application is a Continuation of U.S. patent application Ser. No. 13/447,337, filed Apr. 16, 2012, which claims the benefit of U.S. Provisional Patent Application No. 61/476,016 filed Apr. 15, 2011, the content of each of the aforementioned applications is herein incorporated by reference in their entirety.
This invention was made with government support under grant numbers RR015241 and EB015909, awarded by the National Institutes of Health. The government has certain rights in the invention.
| Number | Date | Country | |
|---|---|---|---|
| 61476016 | Apr 2011 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 13447337 | Apr 2012 | US |
| Child | 15944237 | US |
