WO2016007734A1 - Procédés pour une imagerie médicale moléculaire quantitative et à contraste amélioré utilisant une correction inter-modalités pour une cinétique de traceur différente - Google Patents

Procédés pour une imagerie médicale moléculaire quantitative et à contraste amélioré utilisant une correction inter-modalités pour une cinétique de traceur différente Download PDF

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WO2016007734A1
WO2016007734A1 PCT/US2015/039728 US2015039728W WO2016007734A1 WO 2016007734 A1 WO2016007734 A1 WO 2016007734A1 US 2015039728 W US2015039728 W US 2015039728W WO 2016007734 A1 WO2016007734 A1 WO 2016007734A1
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imaging
modality
medical images
images
contrast agent
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Kenneth M. TICHAUER
Scott C. Davis
Brian William Pogue
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Dartmouth College
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves
    • A61B5/055—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/02—Arrangements for diagnosis sequentially in different planes; Stereoscopic radiation diagnosis
    • A61B6/03—Computed tomography [CT]
    • A61B6/032—Transmission computed tomography [CT]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/02—Arrangements for diagnosis sequentially in different planes; Stereoscopic radiation diagnosis
    • A61B6/03—Computed tomography [CT]
    • A61B6/037—Emission tomography
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/48—Diagnostic techniques
    • A61B6/481—Diagnostic techniques involving the use of contrast agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/52—Devices using data or image processing specially adapted for radiation diagnosis
    • A61B6/5211—Devices using data or image processing specially adapted for radiation diagnosis involving processing of medical diagnostic data
    • A61B6/5217—Devices using data or image processing specially adapted for radiation diagnosis involving processing of medical diagnostic data extracting a diagnostic or physiological parameter from medical diagnostic data
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/52—Devices using data or image processing specially adapted for radiation diagnosis
    • A61B6/5211—Devices using data or image processing specially adapted for radiation diagnosis involving processing of medical diagnostic data
    • A61B6/5229—Devices using data or image processing specially adapted for radiation diagnosis involving processing of medical diagnostic data combining image data of a patient, e.g. combining a functional image with an anatomical image
    • A61B6/5235—Devices using data or image processing specially adapted for radiation diagnosis involving processing of medical diagnostic data combining image data of a patient, e.g. combining a functional image with an anatomical image combining images from the same or different ionising radiation imaging techniques, e.g. PET and CT
    • G—PHYSICS
    • G06—COMPUTING OR CALCULATING; COUNTING
    • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
    • G06T5/00—Image enhancement or restoration
    • G06T5/50—Image enhancement or restoration using two or more images, e.g. averaging or subtraction
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
    • G16H50/30—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for calculating health indices; for individual health risk assessment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/44—Constructional features of apparatus for radiation diagnosis
    • A61B6/4417—Constructional features of apparatus for radiation diagnosis related to combined acquisition of different diagnostic modalities
    • G—PHYSICS
    • G06—COMPUTING OR CALCULATING; COUNTING
    • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
    • G06T2207/00—Indexing scheme for image analysis or image enhancement
    • G06T2207/10—Image acquisition modality
    • G06T2207/10072—Tomographic images
    • G06T2207/10088—Magnetic resonance imaging [MRI]
    • G—PHYSICS
    • G06—COMPUTING OR CALCULATING; COUNTING
    • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
    • G06T2207/00—Indexing scheme for image analysis or image enhancement
    • G06T2207/10—Image acquisition modality
    • G06T2207/10072—Tomographic images
    • G06T2207/10104—Positron emission tomography [PET]
    • G—PHYSICS
    • G06—COMPUTING OR CALCULATING; COUNTING
    • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
    • G06T2207/00—Indexing scheme for image analysis or image enhancement
    • G06T2207/20—Special algorithmic details
    • G06T2207/20212—Image combination
    • G06T2207/20224—Image subtraction
    • G—PHYSICS
    • G06—COMPUTING OR CALCULATING; COUNTING
    • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
    • G06T2207/00—Indexing scheme for image analysis or image enhancement
    • G06T2207/30—Subject of image; Context of image processing
    • G06T2207/30004—Biomedical image processing
    • G06T2207/30024—Cell structures in vitro; Tissue sections in vitro

Definitions

  • the application is also related to the subject matter of PCT Application No. PCT/US 13/24400 filed 01 February 2013, which claims priority to U.S. Provisional application 61,594,862 filed 03 February 2012.
  • This application is also related to PCT Application No. PCT/US 13/20352 filed 04 January 2013, which claims priority to U.S. Patent Application Serial No. 61/583,092, filed 04 January 2012.
  • the disclosures of the above-referenced applications are incorporated herein by reference.
  • contrast agents or tracers are targeted or selective agents, in that they concentrate in, or label, a particular tissue type to a greater degree than they concentrate in, or label, other tissues; targeted agents include fluorescent or radioactive-tracer labeled antibodies, antibodies labeled with radiopaque dyes, as well as other substances— such as radioactive iodine— that are selectively absorbed by particular tissues.
  • Contrast agents which may or may not be targeted, may also include gadolinium and gadolinium-tagged agents, and other paramagnetic contrast agents useful in MRI imaging, as well as microbubble-based agents suitable for ultrasound imaging.
  • Contrast agents are typically specific to a particular modality of imaging.
  • technetium 99m-labeled agents provide significant contrast in tissue when the tissue viewed with a gamma-ray camera, while such agents are typically not visible in, or otherwise affecting, X-Ray based imaging like CT scans.
  • Some targeted agents are taken up and released by tissues at rates that differ with tissue type. This can provide useful information.
  • some targeted tracers such as aminolevulinic acid (ALA), are prodrugs that only become fluorescent after they have been metabolized in tissue; rates of tracer uptake and metabolism of prodrugs can provide useful information about tumor vascularization and metabolism.
  • ALA aminolevulinic acid
  • the pharmaceutical kinetics, or rates of absorption and release of contrast agents and tracers from tissue vary with factors including lipid and water content of tissue, charge distribution on agent molecules, agent molecule sizes, tissue perfusion rates, blood and plasma concentrations, and rates of agent metabolism or excretion.
  • Extending tracer administration-to-imaging time to allow unbound tracer to clear can help in some cases; however, implementing longer wait times (hours and days) is difficult in a clinical setting as multiple visits may be required, and can be counterproductive since signal strength may also be lost over time, making it more difficult to resolve an image. This is particularly challenging for positron emission tomography (PET) scanners, and gamma cameras, which observe radioactive decay of short-lived radiotracers to form an image. Nonspecific uptake also makes single-tracer imaging non-quantitative.
  • PET positron emission tomography
  • An apparatus and method for medical imaging uses a first and second contrast agent, the second agent targeted to a particular tissue type.
  • First images are obtained using the first agent, and second images using the second agent using medical imaging systems.
  • An image processing system is adapted to process the first and second medical images by fitting parameters of a pharmacokinetic model to the first medical images, scaling the fitted parameters to best match nontargeted tissue in the second medical images, executing the pharmacokinetic model to prepare a correction image, and generating corrected medical images by subtracting the correction image from the second medical images.
  • a method of medical imaging includes administering first and second contrast agents; generating first medical images in a first imaging modality using the first contrast agent; generating second medical images using the second contrast agent; and processing the first and second medical images by fitting parameters of a pharmacokinetic model to the first medical images, scaling the fitted parameters to model the second agent, executing the pharmacokinetic model to prepare correction images, and generating corrected medical images by subtracting the correction images from the second medical images; wherein the second contrast agent is an agent configured for uptake by a targeted tissue type.
  • Fig. 1 is an illustration of rate constants Kl, K2, K3, K4, K1U, K2U, for tracer flow between modeled pharmacologic reservoirs in the system.
  • FIG. 2 is a block-diagram illustration of a generic imaging system for which the method of the present invention is applicable.
  • FIG. 3 Plots of the arterial input functions for EGFR-targeted and untargeted fluorescent affibodies measured from carotid artery fluorescence in 6 mice that were used in the simulations for targeted (blue data) and untargeted (red data) tracers
  • Lighter lines represent the respective curves from the individual mice. Darker lines represent mean ⁇ standard deviation of the groups.
  • Fig. 4. Represents uptake curves of the targeted tracer (solid curves) and untargeted tracer (dashed curves) in leg muscle for four mice studied where line type represents results from a separate animal.
  • Fig 5. Represents results of deconvolution of the targeted-untargeted tracer pairs displayed are presented with corresponding colors along with the
  • Fig. 6 illustrates typical "corrected" untargeted tracer uptake curves in the muscle ("Untargeted Ref Tissue”; dashed red curve) and tumor ("Untargeted Tumor”; solid red curve) of Mouse #2 are displayed alongside targeted tracer uptake curves in the muscle ("Tar Ref Tissue”; dashed blue curve) and tumor ("Targeted Tumor”; solid blue curve). The units of these curves are all normalized to the first measured data point.
  • Fig. 7 is a dataflow diagram of the method of image correction. DETAILED DESCRIPTION OF THE EMBODIMENTS.
  • the invention includes methods to account for image-confounding nonspecific uptake of targeted imaging agents in medical imaging.
  • Nonspecific uptake in molecular imaging is perhaps the largest obstacle to what many have predicted will be a revolution in medical imaging (imaging of specific biomarkers).
  • the invention uses a second, non-specific imaging agent, which may be imaged with a second imaging modality, to correct for nonspecific uptake and thus enable recovery of truly biomarker- specific images.
  • Molecular imaging defined as acquiring images of specific molecular biomarkers in tissue, is widely considered the next frontier in medical imaging. Potential uses span almost every area of medicine including imaging of cancer, neurodegenerative diseases, bone health, cardiac function, and others.
  • a molecular imaging protocol generally involves administering to a patient an imaging contrast agent, known as a tracer, targeted to a biomarker of interest, waiting for the tracer to interact with or bind to the target and unbound tracer to be cleared from the vicinity by the body, and then using an imaging system sensitive to the administered agent to acquire images; the images provide a representation of the distribution of the biomarker of interest.
  • These images thus reveal the activity of specific molecular processes in tissue, such as over-expression of receptors on cancer cells, which can be valuable in diagnosis and treatment planning.
  • tracers were chosen to have similar kinetics and thus images obtained from each tracer could be compared directly with one another, as by scaling and subtracting images or applying a dual tracer compartmental modeling for quantitative imaging, to extract information on specific binding.
  • the tracers were also chosen such that both tracers could be imaged with the same imaging modality, such as with fluorescence imaging systems at differing wavelengths.
  • imaging modality such as with fluorescence imaging systems at differing wavelengths.
  • optical modalities generally cannot image deep sub-surface tissue in humans, and most non-optical clinical imaging systems cannot distinguish two tracers in the same tissue at the same time.
  • MRI Magnetic Resonance Imaging
  • PET PET-sensitive contrast agent
  • the method is equally applicable to embodiments using a PET-sensitive contrast agent as a non-targeted tracer and an MRI-sensitive contrast agent as a targeted tracer.
  • Time- dependent image sets from both modalities using first imaging system 154 (Fig. 2), and where imaging system 154 cannot image both tracers, using second imaging system 164.
  • the image sets are acquired, either simultaneously, or nearly simultaneously through interleaved or sequential imaging, over time after administration of the two tracers and stored in image storage 182. Once the image sets are obtained, they are processed by image processor 184 as described below to highlight and resolve tissue targeted by the targeted tracer.
  • MRI-sensitive contrast agents or tracers may incorporate gadolinium into a molecule, and PET-sensitive contrast agents or tracers incorporate a positron-emitting radioactive isotope.
  • the images are obtained on separate MRI and PET scan machines instead of on a dual-mode MRI-PET machine.
  • PET is a modality adapted to image radioisotope concentrations at a first gamma energy equal to the energy of photons emitted by positron-electron annihilations
  • imaging modalities for imaging radioisotope concentrations include gamma camera imaging, and single-photon emission computed tomography (SPECT).
  • SPECT single-photon emission computed tomography
  • Gamma camera imaging and SPECT systems are typically adaptable to image photons of selected energies.
  • one tracer incorporates a non-positron- emitting radioisotope such as gamma-emitting Technetium 99-m (Tc-99m), or Iodine- 123 or Iodine- 131 (1-123 or 1-131 respectively), this contrast agent is imaged either with a gamma camera or a SPECT (single-photon emission computed tomography) camera.
  • a non-positron- emitting radioisotope such as gamma-emitting Technetium 99-m (Tc-99m), or Iodine- 123 or Iodine- 131 (1-123 or 1-131 respectively
  • this contrast agent is imaged either with a gamma camera or a SPECT (single-photon emission computed tomography) camera.
  • the second tracer may be selected from tracers labeled with a different gamma emitting radioisotope, or with a positron emitting radioisotope.
  • one tracer is a gamma-emitting radioisotope and the second tracer a tracer imageable in MRI scanners such as a gadolinium or magnetic nanoparticle-labeled tracer.
  • a first tracer is a gadolinium-labeled or magnetic-nanoparticle tagged tracer imageable in MRI scanners and the second tracer is selected from a tracer labeled with a radioisotope and imageable with PET scanners, SPECT scanners, or gamma cameras, or an iodine-labeled tracers imageable in CT (X-ray computed tomography) scanners.
  • CT X-ray computed tomography
  • the first tracer is a tracer having a short half-life in tissue and imageable in a first imaging modality, and the second tracer is also imageable in the first imaging modality.
  • the first tracer is administered to a subject and a first sequence of images is obtained with the subject in a first position in the imaging system. After sufficient time for the first tracer to leave the subject, the subject is positioned as close as possible to the first position to ensure tissues of interest are in the same location in both the first and second image series, the second tracer is administered, and the second image series is obtained.
  • Step 1 Correct for differences in non-specific kinetics between targeted and untargeted tracers to prepare for cross-modality image processing by:
  • a correction of each with-tracer image is performed to enhance contrast by subtracting out a background pre-tracer image.
  • Step 2 (b) Applying a mathematical deconvolution process to determine a function which corrects for the differences in kinetic behavior between the two tracers. This can be accomplished using either arterial input functions to obtain the deconvolution function, and/or using tracer accumulation in a region devoid of the target to obtain a deconvolution function. The procedure to accomplish this with two tracers follows a similar procedure to what is described in Step 1(a), but including additional analysis as described below:
  • T2 is the targeted tracer
  • a correction of each with-tracer image is performed to enhance contrast by subtracting out a background pre-tracer image.
  • the arterial input function is represented as Ca(t). If the arterial input functions of a targeted tracer, Ca ; x(t), and untargeted tracer, C aj u(t), were to differ as a function of time, t, an exp relate the two functions as follows: (1) where * represents the convolution operator and g(t) is a function that converts C a ,u(t) to C a ,T(t].
  • the function g(t) can be determined from Eq. (1) if the arterial input functions of the targeted and untargeted tracers were measured directly, either via a separate arterial concentration measurement system, or by segmenting arterial flow in the medical images to extract
  • R0I_no_target T (t) RQl_no_targetu(t) * g(t)
  • g(t) can be determined by deconvolving
  • R0I_no_target T (t) by R01_no_targetu(t) is typically an unstable procedure, but one can adopt the approach developed by Diop and St. Lawrence which is based on general singular value decomposition and Tikhonov regularization (Diop M and St Lawrence K, 2012,
  • Step 2 Deconvolution Method For Recovering The Photon Time-Of-Flight Distribution From Time-Resolved Measurements, Optics letters 37 2358- 60). Applying the deconvolution function, g(t), determined either from the arterial input function or from the ROI without targets corrects the image sets of both tracers to one another. These images are now ready for further analysis as described in Step 2.
  • the targeted and untargeted tracer images may be compared directly to extract specific information about the target-to-targeted tracer activity. Assuming the kinetic correction is complete, the two image data sets are corrected to one another such that the only difference is target activity.
  • a simple scaling/subtraction/ratioing method may be used to highlight biomarker activity contrast or kinetic modeling of the tracers for quantitative imaging of biomarker activity, as described in Step2.: [0034] Step 2. Emphasize target-based contrast and/or quantify target- to-targeted tracer activity by:
  • the images of the resulting difference image sequence Idi ⁇ n may be directly displayed, they may also be enhanced to provide anatomical references by, for example, giving the difference images 3 ⁇ 4 ⁇ ) a particular color and superimposing it on a background image, or other image that provides anatomical references, of a different color.
  • Idispiay(n) RED * I ⁇ jif( n ) + GREY * ⁇ ( ⁇ ) ⁇
  • the background image may be derived from one particular image taken with the untargeted tracer.
  • (b) Apply kinetic modeling to time-dependent image stacks of untargeted and targeted tracers to recover quantitative images of target activity: If quantitative information about target activity/concentration is required, a full mathematical model described herein can be applied to the corrected images to calculate images of target-to-targeted tracer activity.
  • the uptake kinetics of the targeted tracer can be represented by a two-tissue compartment 102, 104, plus a blood compartment 106, model (Fig. 1), while those of the untargeted tracer (used to account for non-specific uptake of the targeted tracer) are represented by a one- tissue compartment 120 for each tissue type plus a blood compartment 122 model.
  • one 104 of the two tissue compartments represents targeted tissue, while another compartment 102 represents untargeted tissue of the same organ.
  • Additional reservoirs 105 of untargeted tissues may exist in a patient imaged with targeted tissues having a different set of absorption and release parameters.
  • a system of differential equations can be used to model the concentrations in targeted tissue, as follows in equation 1 :
  • Ca,T, Cf,T, and Cb,T represent the concentrations of targeted tracer in the arterial plasma, in the extravascular space (unbound or “freely associated"), and in the extravascular space and bound to the targeted cell surface receptor, respectively;
  • Kl and k2 are the rate constants governing transport of the targeted tracer between the blood and extravascular space; and k3 and k4 are rate constants governing association and dissociation of targeted tracer binding.
  • C 3 ⁇ 4 u and (3 ⁇ 4u represent the concentrations of the untargeted tracer in the arterial plasma and freely associated in the extravascular space, respectively; and K1 ,U and k2,U are the rate constants governing transport of the untargeted tracer between the blood and extravascular space.
  • BP the binding potential
  • BP is typically the salient parameter of interest as it is proportional to the concentration of targeted receptors available for tracer binding in a region of interest.
  • spatial recovery of BP can provide quantitative images of specific biomarker activity, and this is achievable with tracers that have similar arterial input functions.
  • BP is estimated from Eq. (6) through non-linear fitting, even though the arterial input functions of the two tracers were different. g(t) can also be determined from Eq. (5) if the arterial input functions of the targeted and untargeted tracers were measured.
  • g(t) can be determined by deconvolving
  • mice When the resulting tumors reached a diameter of 3 mm, the skin was removed from the tumors of four mice to measure tracer uptake in the tumor, and the carotids were exposed in the remaining 6 mice for a direct measure of the arterial input functions of the tracers. All mice were injected with an anti-EGFR (targeted) affibody molecule and a negative control (untargeted) affibody, which were labeled with the fluorophores, IRDye-800CW and IRDye-680RD (LI-COR Biosciences, Lincoln, NE), respectively. A mixed solution containing 0.1 nanomoles of each tracer was injected into a tail vein of each mouse.
  • anti-EGFR targeted
  • untargeted untargeted
  • a subject 150 (Fig. 2) having targeted tissue 152 is positioned 202 (Fig. 7) to be imaged by first imaging system 154.
  • a first, targeted, tracer 156 is administered to the subject and a sequence of images of the first modality, the first modality being compatible with the first tracer 156, is obtained and digitized by data acquisition system 180 and stored 206 in an image memory 182.
  • the imaging system 154 is reconfigured to obtain images in a second modality or, in some embodiments, the subject 150 is positioned on a table 160 configured to slide on rails 162 to reposition 210 subject 150 in a second imaging system 164 without disturbing soft tissues of subject 150 or allowing movement.
  • a second, untargeted, tracer 158 is administered 212 and a sequence of images of the second modality, the second modality being compatible with the second tracer 158, is obtained and digitized by data acquisition system 180 and stored 214 in image memory 182.
  • the first and second tracer are mixed and injected simultaneously.
  • the first and second sequences of images are obtained simultaneously, in others the images alternate, and in others the first and second sequences are obtained sequentially without disturbing subject 150 between sequences to avoid shifting soft tissues of the subject.
  • edges are optionally extracted from the higher resolution modality and used in reconstruction of images of the lower resolution modality.
  • data from the higher-resolution modality may be used to correct images of the lower-resolution modality for other factors including attenuation by dense body parts.
  • the image processor 184 executes an image-correction 220 routine 190 from its program memory 186.
  • the image-correction routine includes derivation 222 of pharmacokinetic model parameters for voxels or pixels of the second, untargeted, image sequence by fitting the model parameters to a pharmacokinetic model 188 of the second or untargeted tracer 158 on a per-pixel, or in an alternative embodiment a per- tissue, basis.
  • Untargeted tissue 192 tissue that is expected to be devoid of molecular targets for the targeted tracer 156, in subject 150 is then identified 224.
  • the derived pharmacokinetic model parameters are then scaled 226 by applying equation 6 as described above, such that subtraction of successive images of untargeted tissue 192 as refined by execution of the pharmacokinetic model 188 in an image sequence of the subject taken with the first modality with targeted tracer 156 present are close to null.
  • Images of the first image sequence of the subject are then corrected by executing the pharmacokinetic model 188 to generate a correction image for each time and for each voxel, and subtracting 230 the correction image from the original images of the subject 150 taken with the first modality such that images of targeted tissue 152 are corrected for background first tracer 156.
  • the resulting corrected image sequence is then displayed 232.
  • CT computed x-ray tomography
  • PET positron emission tomography
  • CT contrast agent is used as the untargeted reference to the PET's targeted tracer.
  • CT generally has poor sensitivity to imaging agents, and imaging kinetics using multiple successive CT scans requires a fairly large radiation dose be imparted to the patient.
  • This approach could also be used with hybrid PET-gamma camera imaging, where two radioactive tracers, one being a positron emitter that results in emissions of 51 lkev gamma-ray pairs, and the other being a gamma emitter with a significantly different energy, such as 140kev Tc 99m .
  • Pulse-height analysis can readily distinguish between gamma rays of these widely-separated energies, and coincidence analysis also permits distinguishing between positron-annihilation events and other gamma emissions.
  • a new generation of clinical hybrid systems has been introduced which couples PET and MRI. These scanners are suitable for applying this invention. Since the invention can be used with FDA-approved contrast agents (such as gadolinium DTPA for MRI and any PET tracer) it is possible to test the invention readily using clinical imaging data.
  • the invention focuses on using multiple imaging modalities to image two tracers simultaneously, or nearly simultaneously, and correcting for the differences in tracer kinetics between the two modalities.
  • Our device involves the process of acquiring tracer kinetics of both modalities and applying an algorithmic correction to extract target-specific images.
  • the correction can be applied using only a few CT image acquisitions, this may help reduce patient radiation dosage while providing clinically useful images.
  • a new generation of hybrid clinical imaging systems which combine PET and MRI is gaining popularity. These systems are well-suited to take advantage of the invention.
  • MRI which does not impart ionizing radiation, will be used to provide high resolution images of the non-targeted tracer dynamics, with the corresponding PET system providing co-registered images of targeted tracers.
  • tracers T2 and T3 are administered, where targeted tracers T2 and T3 are targeted for different molecules in normal or abnormal tissues of the subject.
  • Tracers T2 and T3 may, for example, be tracers each embodying an antibody, but with the antibodies targeted at different molecules. Images of tracer accumulation for all three tracers are obtained.
  • Images of both the first targeted tracer T2 and the second targeted tracer T3 are adjusted for tracer kinetics as heretofore described, first adjusted images T2 acl justed °f the first targeted tracer T2 using deconvolution using images obtained using untargeted tracer Tl, then adjusted images T3 acl justed of the second targeted tracer T3 are obtained using deconvolution using images obtained using untargeted tracer Tl ; both sets of adjusted images T2 acl justed an d T3 ac jj U sted are a ls° adjusted for any background, pre-tracer (TO), images as necessary; each set being adjusted independently as heretofore described.
  • TO pre-tracer
  • first targeted tracer T2 may be targeted to a molecule found on normal tissue of a particular organ or tissue type, such as breast tissue or nerve tissue.
  • Second targeted tracer T3 may be targeted to a molecule, such as an estrogen receptor for breast tissue, that is found in tumor tissue arising from the particular organ or tissue type with a concentration differing from a concentration of the same molecule in normal tissue of the same organ.
  • Difference images between T2 ac jj us t e d and T3 adjusted ma Y men prove useful in determining distribution of tumor within the normal tissue, or of determining distribution of a particular drug target within tumor tissue.
  • each of the tracers, Tl, T2, and T3, are independently imaged within the subject, are administered simultaneously, and are distinguished by different emissions energies, such as gamma ray energy from decay of radioactive tracers, or fluorescent emissions energies.
  • one or more tracer is imaged in a different imaging modality, for example but not limitation, TO may be an X-ray dye imaged with a CT scanner, or a gadolinium-labeled molecule imaged with MRI, while T2 and T3 are differently-labeled radioisotopes.
  • one or more of the tracers is administered and imaged not simultaneously but in sequence with the other tracers to allow distinguishing between tracers in images.
  • the invention could be applied to any future hybrid imaging modalities suitable for multi-tracer imaging; as well as to current and future tracers such as those that may be based upon magnetic nanoparticles.
  • An apparatus designated A for performing medical imaging including apparatus configured to administer a first contrast agent and a second contrast agent; a first imaging system operable in a first mode and configured to provide first medical images in a first imaging modality, wherein the first contrast agent is adapted to provide contrast in images of the first modality; imaging apparatus configured to provide second medical images, the imaging apparatus selected from the group consisting of the first imaging system operating in a second mode, and a second imaging system adapted to perform imaging in a second modality, wherein the second contrast agent is adapted to provide contrast in the second medical images while not providing significant contrast in the first medical images, and the first contrast agent is adapted to not provide significant contrast in the second medical images; and an image processing system adapted to process the first and second medical images by fitting parameters of a pharmacokinetic model to the first medical images, identifying a nontargeted tissue in the images, scaling the fitted parameters to best match the nontargeted tissue in the second medical images, executing the pharmacokinetic model to prepare a correction image, and generating corrected medical
  • An apparatus designated Al including the apparatus designated A wherein generating corrected medical images is performed by subtracting the correction image from the second medical images.
  • An apparatus designated AA including the system designated A or wherein the imaging apparatus configured to provide second medical images is a second imaging system adapted to perform imaging in a second modality.
  • An apparatus designated AB including the system designated AA or A 1 wherein the first modality is magnetic resonance imaging (MRI), and the second modality is a modality selected from the group consisting of X-ray computed tomography (CT), gamma camera imaging, positron emission tomography (PET), and single-photo emission computed tomography (SPECT).
  • CT X-ray computed tomography
  • PET positron emission tomography
  • SPECT single-photo emission computed tomography
  • An apparatus designated AC including the system designated AA wherein the first modality is X-ray computed tomography (CT) and the second modality is a modality selected from the group consisting of gamma camera imaging, positron emission tomography (PET), and single-photo emission computed tomography (SPECT).
  • CT X-ray computed tomography
  • PET positron emission tomography
  • SPECT single-photo emission computed tomography
  • An apparatus designated AD including the system designated AA wherein the first modality is a modality adapted to image radioisotope concentrations at a first gamma energy and selected from the group consisting of gamma camera imaging, positron emission tomography (PET), and single-photo emission computed tomography (SPECT).and the second modality is a modality adapted to image radioisotope concentrations at a second gamma energy selected from the group consisting of gamma camera imaging, and single-photo emission computed tomography (SPECT); where the first gamma energy differs from the second gamma energy.
  • the first modality is a modality adapted to image radioisotope concentrations at a first gamma energy and selected from the group consisting of gamma camera imaging, positron emission tomography (PET), and single-photo emission computed tomography (SPECT).
  • the second modality is a modality adapted to image radioisotope concentrations at a
  • An apparatus designated AE including the apparatus designated A wherein generating corrected medical images is performed by applying kinetic modeling to a plurality of images obtained at at least a first and a second time in the first imaging modality with the first contrast agent, and a plurality of images obtained at at least a third and a fourth time of the in the second imaging modality with the second contrast agent.
  • An apparatus designated AF including the apparatus designated AE wherein the kinetic modeling comprises a two-tissue compartment 102, 104, plus a blood compartment 106, model (Fig. 1) for each tissue type for the first tracer, and a one-tissue compartment 120 for each tissue type plus a blood compartment 122 model for the second tracer.
  • An apparatus designated AG including the apparatus designated AE or AF further including firmware in memory for applying a mathematical deconvolution process to determine a function which corrects for the differences in kinetic behavior between the first and second tracers, including additional steps: scaling an image sequence; and applying deconvolution.
  • a method of medical imaging designated B including: generating first medical images using a first medical imaging system using a first contrast agent in in a first imaging modality using the first contrast agent; generating second medical images using a second contrast agent; and processing the first and second medical images by fitting parameters of a pharmacokinetic model to the first medical images, scaling the fitted parameters to model the second agent, executing the pharmacokinetic model to prepare correction images, and generating corrected medical images by subtracting the correction images from the second medical images; wherein the second contrast agent is an agent configured for uptake by a targeted tissue type.
  • a method designated BA including the method designated B wherein the second medical images are obtained using a second imaging system adapted to perform imaging in a second modality different from the first imaging modality.
  • a method designated BB including the method designated B wherein the first modality is magnetic resonance imaging (MRI), and the second medical images are obtained using a second imaging modality selected from the group consisting of X-ray computed tomography (CT), gamma camera imaging, positron emission tomography (PET), and single-photo emission computed tomography (SPECT).
  • CT X-ray computed tomography
  • PET positron emission tomography
  • SPECT single-photo emission computed tomography
  • a method designated BC including the method designated B wherein the first modality is X-ray computed tomography (CT) and the second medical images are obtained using a second modality selected from the group consisting of gamma camera imaging, positron emission tomography (PET), and single-photo emission computed tomography (SPECT).
  • CT X-ray computed tomography
  • PET positron emission tomography
  • SPECT single-photo emission computed tomography
  • a method designated BC including the method designated B wherein the first modality is a modality adapted to image radioisotope concentrations at a first gamma energy and selected from the group consisting of gamma camera imaging, positron emission tomography (PET), and single-photo emission computed tomography (SPECT).and the second medical images are obtained using a second modality to image radioisotope concentrations at a second gamma energy selected from the group consisting of gamma camera imaging, and single-photo emission computed tomography (SPECT); where the first gamma energy differs from the second gamma energy.
  • the first modality is a modality adapted to image radioisotope concentrations at a first gamma energy and selected from the group consisting of gamma camera imaging, positron emission tomography (PET), and single-photo emission computed tomography (SPECT).
  • PET positron emission tomography
  • SPECT single-photo emission computed tomography
  • An apparatus designated C configured for performing medical imaging including apparatus configured to administer a first contrast agent and a second contrast agent, the first and second contrast agent having similar pharmacokinetics; a first imaging system operable in a first mode and configured to provide first medical images in a first imaging modality, wherein the first contrast agent is adapted to provide contrast in images of the first modality; imaging apparatus configured to provide second medical images, the imaging apparatus selected from the group consisting of the first imaging system operating in a second mode, and a second imaging system adapted to perform imaging in a second modality, wherein the second contrast agent is adapted to provide contrast in the second medical images while not providing significant contrast in the first medical images, and the first contrast agent is adapted to not provide significant contrast in the second medical images; and an image processing system adapted with firmware in memory to process the first and second medical images by scaling the first medical images to produce a correction images matching a nontargeted tissue of the first medical images to the nontargeted tissue in the second medical images, and generating corrected medical images by subtracting the correction image
  • Apparatus designated CB including the apparatus designated C or CA wherein the first modality is magnetic resonance imaging (MRI), and the second modality is a modality selected from the group consisting of X-ray computed tomography (CT), gamma camera imaging, positron emission tomography (PET), and single-photo emission computed tomography (SPECT).
  • CT X-ray computed tomography
  • PET positron emission tomography
  • SPECT single-photo emission computed tomography
  • Apparatus designated CC including the apparatus designated C or CA wherein the first modality is X-ray computed tomography (CT) and the second modality is a modality selected from the group consisting of gamma camera imaging, positron emission tomography (PET), and single-photo emission computed tomography (SPECT).
  • CT X-ray computed tomography
  • PET positron emission tomography
  • SPECT single-photo emission computed tomography
  • An apparatus designated D for performing medical imaging including: apparatus configured to administer a first contrast agent and a second contrast agent, the first and second contrast agent having similar pharmacokinetics; a first imaging system operable in a first mode and configured to provide first medical images in a first imaging modality, wherein the first contrast agent is adapted to provide contrast in images of the first modality; imaging apparatus configured to provide second medical images, the imaging apparatus selected from the group consisting of the first imaging system operating in a second mode, and a second imaging system adapted to perform imaging in a second modality, wherein the second contrast agent is adapted to provide contrast in the second medical images while not providing significant contrast in the first medical images, and the first contrast agent is adapted to not provide significant contrast in the second medical images; and an image processing system adapted with firmware in memory to process the first and second medical images by fitting parameters of a pharmacokinetic model to images selected from the first and second medical images, using the pharmacokinetic model to process the first medical images into correction images, and generating corrected medical images from the correction images and

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Abstract

L'invention concerne un appareil et un procédé pour une imagerie médicale, lesquels utilisent un premier et un second agent de contraste, le second agent étant ciblé vers un type de tissu particulier. Des premières images sont obtenues à l'aide du premier agent, et des secondes images à l'aide du second agent par utilisation de systèmes d'imagerie médicale. Un système de traitement d'image est conçu pour traiter les premières et secondes images médicales par adaptation de paramètres d'un modèle pharmacocinétique aux premières images médicales, identification d'un type de tissu non ciblé, mise à l'échelle des paramètres adaptés pour que ces derniers correspondent mieux au tissu non ciblé dans les secondes images médicales, exécution du modèle pharmacocinétique pour préparer une image de correction, et génération d'images médicales corrigées en soustrayant l'image de correction aux secondes images médicales.
PCT/US2015/039728 2012-01-04 2015-07-09 Procédés pour une imagerie médicale moléculaire quantitative et à contraste amélioré utilisant une correction inter-modalités pour une cinétique de traceur différente Ceased WO2016007734A1 (fr)

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US12114988B2 (en) 2008-05-22 2024-10-15 The Trustees Of Dartmouth College Surgical navigation with stereovision and associated methods
US11129562B2 (en) 2008-05-22 2021-09-28 The Trustees Of Dartmouth College Surgical navigation with stereovision and associated methods
US10568535B2 (en) 2008-05-22 2020-02-25 The Trustees Of Dartmouth College Surgical navigation with stereovision and associated methods
US11510600B2 (en) 2012-01-04 2022-11-29 The Trustees Of Dartmouth College Method and apparatus for quantitative and depth resolved hyperspectral fluorescence and reflectance imaging for surgical guidance
US12144667B2 (en) 2012-01-04 2024-11-19 The Trustees Of Dartmouth College Methods for quantitative and enhanced-contrast molecular medical imaging using cross-modality correction for differing tracer kinetics
US11857317B2 (en) 2012-01-04 2024-01-02 The Trustees Of Dartmouth College Method and apparatus for quantitative and depth resolved hyperspectral fluorescence and reflectance imaging for surgical guidance
US12560793B2 (en) 2012-01-20 2026-02-24 The Trustees Of Dartmouth College Method and apparatus for quantitative hyperspectral fluorescence and reflectance imaging for surgical guidance
US11564639B2 (en) 2013-02-13 2023-01-31 The Trustees Of Dartmouth College Method and apparatus for medical imaging using differencing of multiple fluorophores
US12285277B2 (en) 2013-02-13 2025-04-29 The Trustees Of Dartmouth College Method and apparatus for medical imaging using differencing of multiple fluorophores
US11937951B2 (en) 2013-02-13 2024-03-26 The Trustees Of Dartmouth College Method and apparatus for medical imaging using differencing of multiple fluorophores
US12002203B2 (en) 2019-03-12 2024-06-04 Bayer Healthcare Llc Systems and methods for assessing a likelihood of CTEPH and identifying characteristics indicative thereof
US11915361B2 (en) 2019-09-18 2024-02-27 Bayer Aktiengesellschaft System, method, and computer program product for predicting, anticipating, and/or assessing tissue characteristics
US12148163B2 (en) 2019-09-18 2024-11-19 Bayer Aktiengesellschaft Forecast of MRI images by means of a forecast model trained by supervised learning
US11727571B2 (en) 2019-09-18 2023-08-15 Bayer Aktiengesellschaft Forecast of MRI images by means of a forecast model trained by supervised learning
US12310741B2 (en) 2019-09-18 2025-05-27 Bayer Aktiengesellschaft Generation of MRI images of the liver
EP4241672A3 (fr) * 2019-10-11 2023-11-15 Bayer Aktiengesellschaft Accélération d'examens irm
WO2021069343A1 (fr) * 2019-10-11 2021-04-15 Bayer Aktiengesellschaft Accélération d'examens irm
US12394058B2 (en) 2020-04-03 2025-08-19 Bayer Aktiengesellschaft Generation of radiological images

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