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WO2015161363A1 - Anomalies d'imagerie dans une réponse vasculaire - Google Patents

Anomalies d'imagerie dans une réponse vasculaire Download PDF

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Publication number
WO2015161363A1
WO2015161363A1 PCT/CA2015/000274 CA2015000274W WO2015161363A1 WO 2015161363 A1 WO2015161363 A1 WO 2015161363A1 CA 2015000274 W CA2015000274 W CA 2015000274W WO 2015161363 A1 WO2015161363 A1 WO 2015161363A1
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Prior art keywords
voxel
subject
values
vascular response
response
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Inventor
Joseph Fisher
Olivia SOBCZYK
Adrian P. CRAWLEY
Julian POUBLANC
Kevin SAM
Daniel M. MANDELL
David Mikulis
James Duffin
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Priority to CA2946619A priority Critical patent/CA2946619A1/fr
Publication of WO2015161363A1 publication Critical patent/WO2015161363A1/fr
Priority to US15/332,567 priority patent/US11880989B2/en
Anticipated expiration legal-status Critical
Priority to US18/542,450 priority patent/US20240135558A1/en
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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
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0033—Features or image-related aspects of imaging apparatus, e.g. for MRI, optical tomography or impedance tomography apparatus; Arrangements of imaging apparatus in a room
    • A61B5/004—Features or image-related aspects of imaging apparatus, e.g. for MRI, optical tomography or impedance tomography apparatus; Arrangements of imaging apparatus in a room adapted for image acquisition of a particular organ or body part
    • A61B5/0042—Features or image-related aspects of imaging apparatus, e.g. for MRI, optical tomography or impedance tomography apparatus; Arrangements of imaging apparatus in a room adapted for image acquisition of a particular organ or body part for the brain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording for evaluating the cardiovascular system, e.g. pulse, heart rate, blood pressure or blood flow
    • A61B5/026—Measuring blood flow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/40—Detecting, measuring or recording for evaluating the nervous system
    • A61B5/4058—Detecting, measuring or recording for evaluating the nervous system for evaluating the central nervous system
    • A61B5/4064—Evaluating the brain
    • G—PHYSICS
    • G06—COMPUTING OR CALCULATING; COUNTING
    • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
    • G06T7/00—Image analysis
    • G06T7/0002—Inspection of images, e.g. flaw detection
    • G06T7/0012—Biomedical image inspection
    • G—PHYSICS
    • G06—COMPUTING OR CALCULATING; COUNTING
    • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
    • G06T7/00—Image analysis
    • G06T7/30—Determination of transform parameters for the alignment of images, i.e. image registration
    • G06T7/33—Determination of transform parameters for the alignment of images, i.e. image registration using feature-based methods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2576/00—Medical imaging apparatus involving image processing or analysis
    • A61B2576/02—Medical imaging apparatus involving image processing or analysis specially adapted for a particular organ or body part
    • A61B2576/026—Medical imaging apparatus involving image processing or analysis specially adapted for a particular organ or body part for the brain
    • 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
    • G06T2207/20—Special algorithmic details
    • G06T2207/20112—Image segmentation details
    • G06T2207/20128—Atlas-based segmentation
    • 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
    • G06T2207/30016—Brain
    • 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
    • G06T2207/30101—Blood vessel; Artery; Vein; Vascular
    • G06T2207/30104—Vascular flow; Blood flow; Perfusion
    • 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
    • G16H30/00—ICT specially adapted for the handling or processing of medical images
    • G16H30/40—ICT specially adapted for the handling or processing of medical images for processing medical images, e.g. editing

Definitions

  • the present invention relates to methods for imaging an abnormality of vascular reactivity, for example, cerebrovascular reactivity (CVR), broadly defined as an abnormality in a vascular response relative to a control population, as evident from high resolution imaging.
  • CVR cerebrovascular reactivity
  • CVR cerebrovascular reactivity
  • CBF regional cerebral blood flow
  • a surrogate high resolution measure of changes in CBF can be obtained by exploiting the Blood Oxygen Level Dependent (BOLD) effect of magnetic resonance imaging (MRI); and a measurable increase in the end- tidal (end-exhaled) partial pressure of CO2 (PETCO2) may be used as a surrogate measure for the true independent stimulus, the partial pressure of CO 2 in arterial blood (PaC0 2 ).
  • CVR is can then optionally be defined as the per cent change in BOLD signal (arbitrary units) per mmHg change in PaCOi- CVR values can be color coded and superimposed, on the corresponding voxel on an anatomical scan to generate CVR maps.
  • 'steal' a vasodilatory stimulus
  • Steal has been shown to exist in deep white matter in healthy people [Mandeli, 2008] as well as associated with pathology such as arteriovenous malformations [Fierstra, 2011], vasculitis [Han, 2008], steno-occlusive vascular disease [Han, 2011]; and associated with disease in the form of cortical thinning [Fierstra, 2010], cognitive decline [Balucani, 2012; Silvestrini, 2011], and enhanced risk of stroke [Silvestrini, 2000; Markus, 2001],
  • CVR may be considerably reduced, but steal is absent if the stimulated demand fails to exceed its supply capacity.
  • a differential in vasodilatory capacity between vascular territories may not exist and therefore, steal may not occur [Sobczyk 2014).
  • Steal may also not occur if compromised vessels maintain greater than some threshold vasodilatory reserve. Under these conditions, the absolute value of CVR may be less than 'normal' but the extent of reduction cannot be assessed unless the normal range of CVR is known for each anatomical location.
  • CVR maps relies on a qualitative review of possible abnormalities, viewed as inhomogeneities in the CVR maps that appear to differ from the CVR maps of healthy individuals. Such qualitative comparisons require considerable experience for correct interpretation; areas where blunted CVR is present may be misinterpreted as healthy responses.
  • vasoactive stimulus in at least one region of interest (ROI) of the subject's brain.
  • the vasoactive stimulus is in the form of at least one change in a subject's arterial partial pressure of carbon dioxide (each arterial partial termed a PaC0 2 T ).
  • Measured PetC0 2 values are used as a surrogate measure of the true stimulus.
  • the targeted PaC0 2 T (s) is maintained during the course of obtaining input of MR signals. Accordingly, the stimulus is standardized, allowing the severity and distribution of abnormal or reduced vascular response values to be assessed by using statistical scores such as z scores which reveal the severity and distribution of abnormal or reduced surrogate measures of blood flow as revealed by MRI.
  • the invention is directed to method of assessing the severity and distribution of an abnormality or reduction in a subject's vascular response to a vasoactive stimulus in at least one region of interest (ROI) of the subject's brain.
  • ROI region of interest
  • An MRI scanner and a selected MR imaging protocol are used to generate for members of a group of control subjects, a set of vascular response signals representing a non-pathological vascular response to at least one change in the subject's arterial partial pressure of carbon dioxide (each arterial partial pressure of carbon dioxide a PaC02 T ) in at least one common ROI of each control subject's brain.
  • control group need not represent a non-pathological response since any type of status/criterion/parameter can be controlled for for the purposes evaluating a test subject.
  • the vascular response is quantifiable, from a surrogate measure of blood flow, on a voxel by voxel basis, with reference to the voxel coordinates, from MR signals corresponding respectively to each aC02 T in the form of a response value per voxel.
  • the control subject's respective voxel coordinates are co-registered to a standardized space based on a set of anatomic landmarks.
  • a measure of variability of the vascular response values are computed on a voxel by voxel basis.
  • the vascular response values measure at least one of the amplitude of the vascular response and the time course of the vascular response.
  • a mean and standard deviation of the vascular response values for voxels corresponding to the at least one ROI are computed to define, for the control group as a whole, a set of statistical values respectively associated with individual voxels corresponding to the ROI (an atlas).
  • the MR scanner and the selected MR imaging protocol are used to obtain MR signals per voxel corrresponding to the surrogate measure of blood flow for each PaC0 2 T for a test subject.
  • the test subject's response values for individual voxels in the at least one ROI (e.g. as z values) the test subject's response values for individual voxels in the at least one ROI (each voxel co-registered to the standarized space based on the set of anatomic landmarks), relative to the respective computed statistical values e.g. means and standard deviations per corresponding voxel, the severity and distribution of the abnormal or reduced vascular response is revealed.
  • the method may be implemented using a MR scanner and a stand alone CPU or dedicated MR image processor.
  • the processor obtains input of the "abnormal voxel" (pre-defined or user defined via a user interface) coordinates and scores.
  • the processor may employ program code to define a new to ROI.
  • the processor may employ progam code to compare the scores to a threshold value.
  • the processor may employ progam code to compare the scores to scores associated with a disease.
  • the invention is directed to an imaging system for detecting an abnormality in a subject's response to a vasoactive stimulus in at least one region of interest (ROI) of the subject's brain.
  • the vascular response values may measure at least one of the amplitude and time course of the vascular response.
  • the imaging system comprises an MR scanner configurable, using a pre-selected MR protocol, to capture spatially resolved MR signals corresponding to the subject's vasoactive response to a standarized
  • cerebrovascular stimulus comprising at least one targeted change in the subject's arterial partial pressure of carbon dioxide (each arterial PC0 2 a PaC0 2 T ).
  • At least one PaCO ⁇ T is attained from an initial steady state PaC0 2 value.
  • the at least one change in PaC02 is at least one of a series of increments or decrements in the subject's arterial partial pressure of carbon dioxide.
  • the imaging system also comprises a computer programmed to obtain input of the MR signals and implement an algorithm for analyzing the MR signals with reference to a pre-determined surrogate measure of blood flow in the at least one ROI, the pre-determined surrogate measure of blood flow optionally quantifying at least one of the amplitude of the subject's vascular response and a time constant of the subject's vascular response to the at least one PetC0 2 T (at least one change from a steady value or two targeted values)
  • the algorithm includes program code for processing the MR signals with reference to the selected surrogate measure of blood flow for each PetC0 2 T including computing a vasoactive response value per voxel, each voxel co-registered into a
  • the imaging system optionally includes a user interface operable to initiate the aforesaid algorithm and optionally to map the scores back onto an anatomical representation of the standardized space to generate a statistical map of the subject's vascular response to a standardized cerebrovascular stimulus, wherein the probability that subject's vascular response to the standardized
  • cerebrovascular stimulus is pathological is depicted, on a voxel by voxel basis, on the statistical map (e.g. a z map) for example using a color scheme wherein different colors are assigned to different scores such that each color pixel is mapped onto its anatomical 3 dimensional origin.
  • the probability that the vascular response is part of the normal range may be represented by a z score, where high z scores represent lower probability that they are in the normal range and correpondingly higher probability of resulting from underlying pathology.
  • the reference values are a measure of the amount and variability of the vasoactive response and optionally comprise a mean and standard deviation of vascular response values per voxel for a corresponding ROI in a group of control subjects, the vascular response values generated using the pre-selected MR protocol for each same PaC0 2 T and quantifying, on a voxel by voxel basis, the statistical scores e.g. the mean and standard deviation of the selected surrogate measure of blood flow (amplitude or tau or both).
  • the vascular response values are generated from a set of MR signals correponding to the control subjects' respective vascular responses per voxel, the respective voxel coordinates per subject co-registered to a standardized space based on a set of anatomic landmarks.
  • the MR scanner captures MR signals from the brain, as surrogates of brain blood flow, wherein the change in signal corresponds to the subject's vasoactive response to the stimulus.
  • the stimulus is standardized with respect to strength preferably via induction of at least two levels of arterial partial pressure of carbon dioxide (PaC0 2 ), at least one of which is hypercapnic, or greater than the baseline resting level of the subject, and the level of which can be determined directly by arterial blood sampling or noninvasively by its surrogate, the end tidal, or end exhaled partial pressure of carbon dioxide.
  • PaC0 2 arterial partial pressure of carbon dioxide
  • the reference values include a statistical summary of the control subjects' respective vascular response values to each PetC0 2 T .
  • the images represent a change in the blood oxygen level dependent (BOLD) effect of a MR response to a targeted change in a subject's end tidal PC0 2 (PETC0 2 t ).
  • BOLD blood oxygen level dependent
  • the images depict a change in the blood flow as measured by arterial spin labeling MR response to a targeted change in a subject's end tidal PaC0 2 .
  • the program code is operable on a dedicated image processor connected to or forming part of the MR scanner hardware.
  • the MR signals are recorded in a file, optionally a file according to the DICOM standard and processed by a separate computer.
  • the statistical scores are optionally further compared to threshold values per voxel associated with a particular disease, on a voxel by voxel basis.
  • the statistical scores e.g. z scores may be used to identify a new ROI, for example a smaller ROI within an ROI of the subject's brain that was of interest, a priori, in virtue of the pathology being assessed or in virtue of a prior, concurrent or later assessment.
  • the algorithm includes program code for identifying the new ROI.
  • the invention is directed to a computer program product comprising program code/instructions for executing the above-described algorithm, and optionally the reference values and/or program code for accessing the computer remotely to compare a subject's MR signals corresponding to the selected surrogate measure of blood flow with reference values and same targeted arterial partial pressures of carbon dioxide.
  • the computer program product comprises program code for producing a color coded statistical map and/or program code for identifying a new ROI.
  • the invention is directed to a non-transitory computer readable medium comprising program code for executing the above-described algorithm, and optionally the reference values and/or program code for accessing the computer remotely to compare a subject's MR signals corresponding to the selected surrogate measure of blood flow with reference values and same targeted arterial partial pressures of carbon dioxide.
  • the computer program product comprises program code for producing a color coded statistical map and/or program code for identifying a new ROI.
  • the reference scores are part of an atlas prepared for each a series of targeted increments in a subject's arterial partial pressure of carbon dioxide.
  • the invention is directed to a method of characterizing an abnormality in a subject's vascular response to a vasoactive stimulus in at least one region of interest (ROI) of the subject's brain comprising the steps of: a) using an MRI scanner and a selected MR imaging protocol to generate for members of a group of control subjects, a set of vascular response signals representing a non-pathological vascular response to at least one change in the subject's arterial partial pressure of carbon dioxide (each arterial partial pressure of carbon dioxide a PaC0 2 T ) in at least one common ROI of each control subject's brain, wherein the vascular response is quantifiable, from a surrogate measure of blood flow, on a voxel by voxel basis, with reference to the voxel coordinates, from MR signals corresponding respectively to each PaC0 2 T in the form of a response value per voxel;
  • ROI region of interest
  • the method further comprises the step of color-coding the z values and mapping the color-coded values back onto an anatomical representation of the standardized space to produce a z map.
  • the invention is also directed to such z maps and their use as a diagnostic tool.
  • the co-registered MR images are full brain images defining a substantially full set of potential ROIs.
  • the standardized cerebrovascular stimulus is a vasodilatory stimulus.
  • the vasodilatory stimulus is at least one targeted increase in the subject's end tidal PC02, optionally from a steady state PetC0 2 or a previously targeted value.
  • the stimulus is a series of increment or decrements in a subjects arterial partial pressure of carbon dioxide (a so-called ramp sequence).
  • the reference values in an atlas are generated using a ramp sequence.
  • statistical maps such as z maps can be used to interpret interval differences and values for gain, phase and coherence emerging from a transfer function analysis.
  • BOLD blood oxygen level dependent
  • PETC0 2 end tidal PC0 2
  • CVR ⁇ S / ⁇ PETC0 2
  • the set of control subjects are selected on the basis that they report being free of neurological disease.
  • control subjects are matched for a parameter that is appropriate for the condition being examined in a patient.
  • patient is used broadly to define a subject being tested with reference a selected control population.
  • the set of control subjects are matched for at least one of age and gender.
  • the invention is directed to a method of assessing the severity and distribution of an abnormality or reduction in a subject's vascular response to a vasoactive stimulus in at least one region of interest (ROI) of the subject's brain, comprising the steps of: a) using an MRI scanner and a selected MR imaging protocol to generate for members of a group of control subjects, a set of vascular response signals representing a control (e.g.
  • vascular response to at least one change in the subject's arterial partial pressure of carbon dioxide (each arterial partial pressure of carbon dioxide a PaC0 2 T ) in at least one common ROI of each control subject's brain, wherein the vascular response is quantifiable, from a surrogate measure of blood flow, on a voxel by voxel basis, with reference to the voxel coordinates, from MR signals corresponding respectively to each PaC0 2 T in the form of a response value per voxel;
  • the method excludes the MR scans (for one of or for both the test and control subjects) and optionally also excludes preparation of the reference value atlas from the MR signal data (D1COM), the method comprising, for example, the steps required to compute z scores, namely: (a) obtaining input of the test subject's vascular response values per voxel; (b) obtaining input of the 15 000274
  • the reference values comprise statistical values, for example, a mean and standard deviation of respective control subject's vascular response values per voxel for a corresponding ROI in each member of the group of control subjects, the reference values and the test subject's vascular response values per voxel derived from MR signals obtained from an MR scanner using a pre-selected MR protocol and including respective voxel coordinates co-registered to a
  • each arterial partial pressure of carbon dioxide (each arterial partial pressure of carbon dioxide a PaC0 2 T ) in at least one common ROI of each individual subject's brain, wherein the vascular response is quantified, from a surrogate measure of blood flow, on a voxel by voxel basis, the MR signals quantifying at least one of the amplitude of the individual subject's vascular response and a time constant of the individual subject's vascular response to the each PaC0 2 T , wherein the scores e.g. z scores, identify the severity and distribution of an abnormality or reduction in the test subject's vascular response to the vasoactive stimulus.
  • test-subject's vascular response values corresponding to at least one region of interest (ROI) of the test subject's brain After obtaining input of the test-subject's vascular response values corresponding to at least one region of interest (ROI) of the test subject's brain, obtaining input of reference values for each voxel in the ROI (an atlas) for a group of control subjects (e.g. by interrogating a database), and scoring the test subject's
  • the scores and voxel coordinates may be compared to a threshold value, for example to define the extent and distribution of an abnormality.
  • the vascular response values are a measure of a delay in vascular response to the at least one change in the subject's arterial partial pressure of carbon dioxide, wherein at least one statistical value is determined for each respective voxel using a transfer function analysis. For example, a polynomial function may be computed to match the MR signals constituting the vascular response.
  • the at least one statistical value is tau
  • a standardized transfer function analysis for all subjects optionally employing a mono-exponential dispersion function to generate an atlas of tau values.
  • the atlas response values are rank ordered on a voxel by voxel basis.
  • the test subject response values per voxel are assigned a rank score following the rank order to generate a rank score map.
  • a log transformation of the respective (voxel by voxel) vascular response values for the individual control subjects shows that the values are generally normally distributed-
  • the individual control subject vascular response values and patient vascular response values are transformed, on a voxel by voxel basis, by taking the log of the values, and wherein a mean and SD of the control subjects respective vascular responses log transformed values is computed on a voxel by voxel basis to generate an atlas, and wherein the patient's respective vascular responses log transformed values are respectively scored with a z value.
  • the method further comprises the step of color coding the scores and mapping the color-coded scores back onto an anatomical representation of the standardized space.
  • test subject and the control subjects are each scanned on one occasion to obtain a set of response values per voxel (A) and then each re- scanned at least once after an interval to obtain another set of response values per voxel (B).
  • a voxel mean and standard deviation with respect the quantum and variability of the respective differences e.g.
  • the invention is directed to a method of assessing the severity and distribution of an abnormality or reduction in a subject's vascular response to a vasoactive stimulus, in at least one region of interest (ROI) of the subject's brain, comprising the steps of: a) using an MRI scanner and a selected MR imaging protocol to generate for members of a group of control subjects, a first set (A) of vascular response signals representing a control (e.g.
  • vascular response to at least one change in the subject's arterial partial pressure of carbon dioxide (each arterial partial pressure of carbon dioxide a PaC02 T ) in at least one common ROI of each control subject's brain, wherein the vascular response is quantifiable, from a surrogate measure of blood flow, on a voxel by voxel basis, with reference to the voxel coordinates, from MR signals corresponding respectively to each PaC02 T in the form of a response value per voxel; b) re-testing each control subject at least once after an interval at each PaC0 2 T using the MRI scanner and the selected MR imaging protocol to obtain at least one second set (B) of the vascular response signals representing at least one additional measurement of each control subject's (e.g.
  • vascular response per voxel a value representing the difference between the respective test vascular response values and the re-test vascular response values for each individual control subject (consistently A image values minus B image values, or consistently B image value minus A image values), on a subject by subject and voxel by voxel basis, for voxels corresponding to the at least one ROI;
  • the method excludes the scans (test and control subjects) and optionally also excludes preparation of the reference value atlas, the method comprising the steps required to compute z scores, namely: (a) obtaining input of the A and B values per voxel (or at least the differences per voxel) for the test subject ; (b) obtaining input of means and standard deviations per voxel of the differences between the A and B scores for the control group (the reference values); and computing the z values.
  • the method further comprises the step of color-coding the z values and mapping the color-coded values back onto an anatomical representation of the standardized space to produce a z map.
  • the co-registered voxel coordinates represent full brain images defining a substantially full set of potential ROIs.
  • the standardized cerebrovascular stimulus is a vasodilatory stimulus.
  • a vasoactive stimulus can optionally be a vasoconstrictive stimulus
  • the vasodilatory stimulus is at least one targeted increase in the subject's end tidal PCO2 relative to an steady state baseline PaC02 or a previous targeted value which may optionally be an initial reduction in PC0 2 .
  • BOLD blood oxygen level dependent
  • MRI magnetic resonance imaging
  • the set of control subjects are selected on the basis that they report being free of neurological disease.
  • the set of control subjects are matched for at least one additional parameter that that defines a preferred subset of control subjects for the patient population for whom an assessment of an abnormality in vascular response is needed.
  • the set of control subjects are matched for at least one of age and gender.
  • the set of control subjects are selected on the basis that they report being non-smokers.
  • the invention is directed to a reference atlas of response values as generated in any manner defined above using a series of increments in a subject's arterial partial pressure of carbon dioxide as a stimulus, and to the use of such an atlas as a diagnostic tool in aiding of diagnosing a condition associated with an abnormal vascular response, for example a vascular disease or disease manifesting an abnormality in a vascular response.
  • the atlas is generated using a sequential gas delivery circuit (physical or virtual) wherein end tidal partial pressure of carbon dioxide are used as surrogates for targeted arterial partial pressures of carbon dioxide.
  • the invention is directed to a neuro-imaging assessment method in aid of diagnosing at least one of the existence, location, deterioration and amelioration of a brain disorder associated with abnormal vascular reactivity (i.e. any abnormal vascular response including an abnormality in the amplitude and/or time course of the response), for example a
  • the neuro-imaging assessment protocol of the present invention enables images to be produced from which such diagnostic assessments may be carried out and/or confirmed.
  • the organ is brain and the invention provides a novel cerebrovascular reactivity assessment protocol for producing a reference atlas, for example an atlas of non-pathological
  • the invention provides for a method and for the use such an atlas of non-pathological cerebrovascular reactivity to produce brain imaging results e.g. neuro-imaging results from which a subject in need of assessment of abnormal cerebrovascular reactivity can be assessed for the abnormality.
  • the method optionally comprises producing a reference atlas and comparing voxel by voxel test vascular response value of a patient to the corresponding reference atlas value by scoring those values, preferably in a manner that accounts for relative departure of the test value from a quantity describing a characteristic value (e.g. mean/SD for normal distributions of value or normal distributions of log values) such as to account for the variability or distribution of the control values.
  • a characteristic value e.g. mean/SD for normal distributions of value or normal distributions of log values
  • the invention is directed to a diagnostic tools in the form of a neuro-image and other visual depictions such as graphs derived from such images that incorporate statistical transformations of MR signals generated in response to at least one targeted change in a subject end-tidal PC0 2 .
  • the invention is directed to a diagnostic tools in the form of a neuro-image and other visual depictions such as graphs derived from such images that incorporate statistical transformations of MR signals generated in response to at least one targeted change in a subject end-tidal PC0 2 .
  • the invention is directed to a diagnostic tools in the form of a neuro-image and other visual depictions such as graphs derived from such images that incorporate statistical transformations of MR signals generated in response to at least one targeted change in a subject end-tidal PC0 2 .
  • the invention is directed to a diagnostic tools in the form of a neuro-image and other visual depictions such as graphs derived from such images that incorporate statistical transformations of MR signals generated in response to at least one targeted change in a
  • cerebrovascular reactivity response map e.g. in the form a z map, tau z map or ID z map as described herein.
  • the organ is brain and the invention is directed to a diagnostic tool comprising color-coded z values mapped onto an anatomical representation of a standardized 3D map of at least one region of interest (ROI) of the brain, the z values and 3D map characterized in that a standardized set of MR imaging protocols are employed to generate for members of a group of control subjects, a set of CVR response signals depicting a non-pathological CVR response, in at least one common ROI of each control subject's brain, wherein the CVR response is a reaction to a standardized vasoactive stimulus, and wherein the CVR response is quantifiable from images corresponding to the response signals, on a voxel-by-voxel basis, in the form of CVR response value per voxel; and wherein
  • a standardized algorithm is used to co-register the respective control subject images to a standardized space based on a set of anatomic landmarks; c) a computation, for the set of control subjects, on a voxel by voxel basis, of a mean and standard deviation of the CV response values for voxels
  • the MR scanner and the standardized set of MR imaging protocols is used to measure a CVR response for a subject in need of an assessment of an abnormality in CVR, employing the standardized vasoactive stimulus by scoring the respective responses for individual voxels jn the at least one ROI, relative to the computed mean and standard deviation, using z values.
  • z values can be generated for test subjects that are based on a measurement of a plurality of CVR test values, on a voxel by voxel basis, for each respective control subject.
  • Multiple CVR values per control subject are obtained from a plurality of imaging tests generated using a standardized stimulus and therefore reflect expected test/re-test variability in CVR
  • the successive tests are preferably conducted on different days and optionally at different times of day, such that the plurality of variant values reflect primarily the inevitable variations corresponding to normal variations in physiology and in the technology (even despite using a single scanner), over time.
  • the different values may also reflect in minor part differences due to other categories influences (e.g. unidentified sources of small variation or, identifiable sources of small variation of the type not generally subject to practical control).
  • the standard CVR atlas may reflect this retest values in the means and standard deviation per voxel.
  • the probative value of such re-test values can be accentuated by generating a specialized reference atlas (an Interval Difference atlas) in which the control group means and standard deviations are calculated with respect to intra-subject differences e.g. say between the two test values for a subject which are subtracted from one another.
  • the intra-subject test/re-test variability is important for assessing a patient's change in CVR per voxel against a backdrop of normal re-test variability.
  • ID-z values may be used to compute ID z values for a given control or diseased subject, and for creating for the group of subjects, an atlas of test-retest value differences, on a voxel by voxel basis. This enables an attribution of the statistical probability that changes in CVR to true interval change in pathophysiology.
  • resulting ID-z values may be as reference maps to monitor progression of the disease over time or responses to treatment.
  • the standardized cerebrovascular stimulus is a vasodilatory stimulus.
  • the method is used in aid of diagnosing a neurological disorder
  • the vasodilatory stimulus is a surrogate measure of the subject's arterial PC0 2 (PetC0 2 ), the surrogate measure optionally an end tidal partial pressure of carbon dioxide measured on a breath by breath basis.
  • the stimulus is preferably controlled by targeting at least one Increase (relative to a subject's baseline steady state value or a previously targeted value), in a subject's end tidal PCO2-
  • the standardized stimulus optionally provides for a subjects baseline PetC0 2 to be increased to a targeted value and returned to baseline, and optionally increased again to the same targeted value. Variations on such standardized protocols would be apparent to those skilled in the art of manipulating arterial blood gases.
  • CBF cerebral blood flow
  • BOLD Blood Oxygen Level Dependent
  • MRI magnetic resonance imaging
  • the images depict a change in the blood flow as measured by arterial spin labeling MR response to a targeted change in a subject's end tidal PaC0 2 .
  • control subjects are preferably free of neurological disease and optionally also non-smokers.
  • control subjects are age and/or gender matched.
  • the subjects can be matched with respect to a wide variety of parameters including underlying disease, the use or non-use of certain medications etc.
  • the z maps or ID standardized z values are optionally employed for the detection of areas of paradoxical reductions in blood flow following the application of the vasodilator/ stimulus ('steal').
  • parallel increases in blood flow elsewhere may also be indicative of an abnormality in a vascular bed.
  • data can be transformed by taking the log of a measure and tested for normal distribution. If the logs are normally distributed, then the mean and SD of the logs are computed. The test voxel is then also transformed to log value and then scored with a z value.
  • the invention is directed to a method of using blood flow correlated high resolution imaging signals for characterizing an abnormality in a vascular response to a standardized vasoactive stimulus in at least one region of interest (ROI) in an organ, the method comprising the steps of: a) using an high resolution imaging device and a standardized set of imaging protocols to generate, for respective members of a group of control subjects, a vascular response signal depicting, for each voxel corresponding to the at least one ROI, a control group member's vascular response to a standardized vasoactive stimulus, wherein the vascular response for the ROI for each control group member is quantifiable from images corresponding to the respective individual voxel response signals;
  • the method further comprises the step of color-coding the scores and mapping the color-coded scores back onto an anatomical representation of the standardized space to produce a vascular response map of the at least on ROI.
  • the scores are z-scores and wherein the map is a z-map.
  • the organ is brain.
  • the high resolution imaging device is an MRI device, wherein the co- registered images are magnetic resonance images.
  • the co-registered MR images are full brain images defining a substantially full set of potential ROIs.
  • the standardized cerebrovascular stimulus is a vasodilatory stimulus.
  • the vasodilatory stimulus is at least one targeted increase in the subject's end tidal PC0 2 from a steady state PetC02.
  • the images correspond to signals representing a change in a blood oxygen level dependent (BOLD) MRI response to a targeted increase in a subject's end tidal PCO2 (PETCO2), the vascular response values optionally representing a change in BOLD MRI signal ( ⁇ S), in response to a standardized increase in the PETC0 2 (A S / ⁇ PETCO2)- AS mentioned above, ASL may be used in to measure a change in blood flow in response to a standardized PC0 2 stimulus.
  • BOLD blood oxygen level dependent
  • PETCO2 end tidal PCO2
  • the vascular response values are a measure of a delay in the vascular response to the standardized vasoactive stimulus, the at least one statistical value determined for each respective voxel using a standardized transfer function analysis wherein a polynomial function is computed to match the vascular response signal data.
  • the at least one statistical value is tau, the standardized transfer function analysis employing a mono-exponential dispersion function (exemplified herein) to generate an atlas of tau values.
  • the atlas response values are rank ordered on a voxel by voxel basis and wherein the corresponding patient response values are assigned a rank score following the rank order to generate a rank score map.
  • a log transformation of the respective (voxel by voxel) vascular response values for the individual control subjects shows that the values are generally normally distributed and wherein the individual control subject vascular response values and patient vascular response values are transformed, on a voxel by voxel basis, by taking the log of the values, and wherein a mean and SD of the control subjects respective vascular responses log transformed values is computed on a voxel by voxel basis to generate an atlas, and wherein the patient's respective vascular responses log-transformed values are respectively scored with a z value.
  • each of the members of the group of control subjects are selected to represent healthy individuals exhibiting a non-pathological vascular response to the standardized vasoactive stimulus in the at least one ROI.
  • the control group can be represented by any number of different criteria.
  • the invention is directed to a neuro-imaging assessment method in aid of diagnosing at least one of the existence, location, deterioration and amelioration of a brain disorder associated with abnormal vascular reactivity, for example a cerebrovascular disorder.
  • the neuro-imaging assessment protocol of the present invention enables images to be produced from which such diagnostic assessments may be carried out and/or confirmed.
  • the invention provides a novel cerebrovascular reactivity assessment protocol for producing an atlas of non-pathological cerebrovascular reactivity.
  • the invention provides a method of using such an atlas of non-pathological cerebrovascular reactivity to produce neuro-imaging results from which a subject in need of assessment of abnormal cerebrovascular reactivity can be assessed for the abnormality.
  • the invention is directed to a diagnostic tool in the form of a neuro-image and other visual depictions such as graphs derived from such images that incorporate statistical values derived from MR signals generated in response to at least one targeted change in a subject's end-tidal PC0 2 .
  • the invention is directed to a cerebrovascular reactivity response map in the form a z map or ID z map, or tau z map as described herein.
  • the invention is directed to a diagnostic tool comprising color-coded z values mapped onto an anatomical representation of a standardized 3D map of at least one region of interest (ROI) of an organ e.g. brain, the z values and 3D map characterized in that a standardized set of imaging protocols are employed to generate for members of a group of control subjects, a set of vascular response signals depicting a non- pathological CVR response, in at least one common ROI of each control subject's organ of interest, wherein the vascular response is a reaction to a standardized vasoactive stimulus, and wherein the vascular response is quantifiable from images corresponding to the response signals, on a voxel-by- voxel basis, in the form of vascular response value per voxel;
  • ROI region of interest
  • a standardized algorithm is used to co-register the respective control subject images to a standardized space based on a set of anatomic landmarks; c) a computation, for the set of control subjects, on a voxel by voxel basis, of a statistical value describing the quantity and variability of vascular response values associated with corresponding voxels of the standardized space, optionally a mean and standard deviation of the vascular response values for voxels corresponding to the at least one ROI is used; d) the MR scanner and the standardized set of MR imaging protocols is used to measure a CVR response for a subject in need of an assessment of an abnormality in CVR, employing the standardized vasoactive stimulus by scoring the respective responses for individual voxels in the at least one ROI, relative to the e.g. computed mean and standard deviation, using e.g. z values.
  • the invention is directed a method of assessing the severity and distribution of an abnormality or reduction in a test subject's vascular response to a vasoactive stimulus in at least one region of interest (ROI) of the subject's brain, comprising the steps of:
  • Figure 1 is a series of axial slices for a normal cohort atlas displaying the spatial distribution of (A) mean CVR values coloured according to the scale shown on the right in % BOLD change / mmHg PETC0 2 change and (B) coefficient of variation (CV) values with colour scale on right in percent.
  • Figure 2 is a set of axial slices displaying the spatial p-value results of an
  • Figure 3 is a healthy subject's CVR map. An axial slice is shown on the left displaying the spatial distribution of CVR values coloured according to the scale shown on the right in % BOLD change / mmHg PETC0 2 change. The
  • FIG. 3 illustrates the extent of expected high statistical abnormality, as a result of physiologic, technical, and anatomical variation in the subject as well as errors in matching of voxels during co-registration.
  • Figure 4 depicts magnetic resonance angiograms, CVR maps and corresponding z maps for a sample set of 5 patients with varying levels of carotid artery (CA) disease.
  • the CVR maps were analyzed by z scoring of the CVR map relative to a normal atlas. This figure is supplemented with a table, Table 2 ( Figure 6) that provides additional information and commentary for each subject.
  • Dx. diagnosis; MRA - magnetic resonance angiogram).
  • Figure 5 depicts magnetic resonance angiograms, CVR maps and corresponding z maps for a sample set of 4 patients with Moyamoya disease and one patient with idiopathic intracranial hypertension.
  • the CVR maps were analyzed by z scoring the CVR map relative to a normal atlas.
  • MRA magnetic resonance angiogram
  • Figure 6 is a table (Table 2) providing additional information about the patients for whom magnetic resonance angiograms, CVR maps and corresponding z maps are provided in Figures 4 and 5 (Abbreviations: ACA, anterior cerebral artery; EC-IC, external carotid to internal carotid; GM, gray matter; Hx, History; ICA, internal carotid artery; L, Left; R right; MCA, middle cerebral artery; MM,
  • Figure 7 is summary table (Table 3) comparing CVR maps and z-maps.
  • Figure 8 shows CVR maps for a male subject tested on two different sessions 14 days apart.
  • Figure 9 are Bland-Altmann plots of CVR for between-day reproducibility for gray (a) and white (b) matter regions. The Bland-Altman analysis compares the CVR values for gray and white matter obtained on the different days establishing that the mean difference between days for gray matter was 0.0013
  • Figure 10 depicts results for the application of a sample ID atlas to assess the changes in CVR over time in a healthy control subject (not included in the ID atlas) demonstrating that the majority of difference between day 1 and day 2 in this healthy subject ⁇ 1.0 SD as expected.
  • Figure 11 presents angiogram, CVR and ID z maps for an axial slice showing the spatial distribution of CVR values and the associated z-maps at z value thresholds of 0.5 and 1.0. Imaging data from a 38 year old female with moya moya cerebrovascular disease who underwent 2 CVR studies pre, and 6 months post right EC-IC bypass, 6 months apart. A) The magnetic resonance angiogram and CVR maps for an axial slice showing the spatial distribution of CVR values B. The temporal z-maps of the two CVR maps.
  • Figure 12 is a Table describing the distribution of age and sex of the cohort of 46 control subjects.
  • Figure 13 presents in an upper left panel a series of deconvolved input signals - PETC0 2 (red lines) to match BOLD signal (black line) in one voxel (crosshairs) from which ⁇ is calculated.
  • the upper right panel is a CVR map.
  • Lower left panel shows the amplitude of response as calculated from the matched deconvolved function.
  • Lower right panel is the ⁇ map.
  • Figure 14 presents CVR and tau maps and their respective z maps in a patient with right carotid artery stenosis.
  • Figure 14 shows an abnormal time response (tau and tau z values) in areas with normal or mildly abnormal CVR amplitude and z values (outlined, arrows).
  • Figure 15 is a graph illustrating a change of amplitude of a BOLD signal (CBF signal) (Y axis) as a function of PCO2 in mmHg (X axis) and time (z axis) for robust (blue), dampened (red) and paradoxical (orange) responses.
  • CBF signal BOLD signal
  • Figure 16A-E provide illustrations characterizing the use of transfer function analysis to label each voxel as per gain and phase lag.
  • Means and SD are computed and then a z map is generated for our test subject of gain and lag phase. Theoretically, these values should correspond to CVR and T respectively.
  • Figure 16B-16D images show that indeed they look very similar (compare CVR line to Gain line in Figure 16B; and phase lag line slide 16B to ⁇ line in Figure 16C.
  • Figure 16D compares images of amplitude from CVR amplitude measured (first line), amplitude calculated from ⁇ dispersion (second line), and gain using FTA (fourth line).
  • Figure 17a is a flow chart showing a series of steps useful for producing vascular response data for a subject (control or patient) according to an embodiment of the invention.
  • Figure 17b is table describing the nature and function of each step presented in Figure 17a.
  • Figure 18a is a flow chart showing a series of steps useful for producing z maps for a subject according to an embodiment of the invention. These z-map generation steps may applied to CVR, to amplitude, tau, gain, phase, coherence, interval differences etc.
  • Figure 18b is table describing the nature and function of each step presented in Figure 18a.
  • Figure 9a is a flow chart showing a series of steps useful for producing tau response values per voxel in at least one ROI for a subject according to an embodiment of the invention.
  • Figure 19b is table describing the nature and function of each step presented in Figure 19a.
  • Figure 20a is a flow chart showing a series of steps useful for conducting a transfer function analysis for a subject according to an embodiment of the invention.
  • Figure 20b is table describing the nature and function of each step presented in Figure 20a.
  • Figure 21a is a flow chart showing a series of steps useful for producing Interval Difference (ID) z maps for a subject according to an embodiment of the invention.
  • Figure 21b is table describing the nature and function of each step presented in Figure 21a. Detailed Description of Preferred Embodiment
  • a reference atlas can be made for each the vascular response values exemplified herein, the values matched to a set of particular targeted arterial partial pressures of carbon dioxide.
  • the reference atlases can be made from ⁇ and phase lag, for amplitude of CVR , for interval differences etc. Each can be used to generate a z map-
  • co-register means transforming image data onto common coordinates of a standard brain using an alignment algorithm that standardizes brain size while optimizing alignment of a set of key anatomical structures.
  • vascular reactivity * and the related term cerebrovascular reactivity (CVR) is used broadly to refer any vascular response to a standardized vasoactive stimulus, which vascular response may be a change in amplitude of the response, the time course of the response etc.
  • Vascular response values may be a measure of the amplitude of the response (i.e. a measure of amplitude alone, wherein amplitude is revealed, for example, by allowing 3 time constants in the progress of the response to be attained before modifying the PaC0 2 T or where a ramp stimulus is employed e.g. equal size increments in PaC0 2 T and equal time intervals, the true amplitude of the response will be substantially revealed where, for example, two time constants in the progress of the response are attained before the next incremental change in PaC0 2 T .
  • a user may prospectively or retrospectively define a voxel as "abnormal" with reference to at least one of: (1) the size of the vasoactive stimulus or change in stimulus (e.g. the degree of upward departure of the PaC0 2 T from a normal baseline value for the subject) used to reveal the abnormality; (2) the size of the z score (e.g. 2 to 3 standard deviations relative to the mean).
  • the size of the vasoactive stimulus or change in stimulus e.g. the degree of upward departure of the PaC0 2 T from a normal baseline value for the subject
  • the size of the z score e.g. 2 to 3 standard deviations relative to the mean.
  • the time course of the response may be revealed with a step change (e.g. a targeted increase within the range of approximately 5 to 12 mm of Hg, for example 10 mm of Hg in PetC0 2 ) in the stanadardized vasoactive stimulus by monitoring the time course of the response to the step change.
  • a step change e.g. a targeted increase within the range of approximately 5 to 12 mm of Hg, for example 10 mm of Hg in PetC0 2
  • At least one step change within this range or a ramp with small increments in PaC02 T from baseline e.g. to baseline + 10 mm of Hg may be used to assess the amplitude of the response.
  • each PaC0 2 T is maintained in the course of obtaining input of the MR signals. Accordingly the stimulus is standarized for control and test subjects and the true nature of the response is revealed. In this manner, comparing test subjects with a control subject atlas reveals the severity and distribution of an abnormal or reduced vascular response.
  • a CVR map might show a mildly abnormal response for a voxel that is hard to judge as a probable indicator of disease, the precision of the stimulus allows a more conclusive determination of abnormality to be revealed.
  • statistical maps such as z maps reveal the paramount importance of this standardized PaC0 2 T stimulus. Furthermore a reduction in the vasoactive response, not visible in a CVR map, will be be revealed as abnormal and hence as a region that might harbour an underlying pathology.
  • high resolution with used with reference to imaging modality or device refers to an imaging modality enjoying a spatial resolution of 1 cubic centimeter or smaller.
  • the term includes MRI imaging modalities (for example BOLD, T2*, ASL) and other imaging modalities well known as being useful to quantify surrogate measures of blood flow (CT, SPECT, PET).
  • CT computed tomography
  • SPECT computed tomography
  • PET PET
  • vasoactive stimulus Is accomplished in the manner described herein.
  • the standardized vasoactive stimulus is one or more targeted arterial partial pressures of carbon dioxide.
  • the standardized vasoactive stimulus is a series of increments or decrements in a subject's arterial partial pressure of carbon dioxide as described in our co-pending U.S. Patent
  • a measurable increase in the end-tidal (end-exhaled) partial pressure of C0 2 may be used as a surrogate measure for the true independent stimulus, the partial pressure of CO2 in arterial blood (PaCQ2).
  • a targeted end tidal partial pressure of carbon dioxide is achieved via sequential gas delivery using a specialized re-breathing circuit or a virtual sequential gas delivery circuit (see our co-pending application No.US/2015/0034085, originally published as WO/2013/138910).
  • CVR may be defined as the per cent change in BOLD signal (arbitrary units) per mmHg change in PaC0 2 .
  • CVR values for subjects in need of assessment of cerebrovascular reactivity in at least one ROI are assigned color-coded z values based on computations of mean (+/- SD) CVR values, preferably computed on a voxel by voxel basis, for a group of control individuals using images co-registered to a standardized space based on anatomical markers and standardized parameters.
  • the color-coded Z values representing the number of standard deviations from the mean are then superimposed, on the corresponding voxel on an anatomical scan to generate Z maps.
  • CVR was measured as the blood oxygen level dependent (BOLD), magnetic resonance imaging (MRI) response to a
  • CVR maps from 46 healthy subjects were co-registered into a standard space and mean and standard deviation (SD) was measured for each voxel to form the normal CVR atlas.
  • CVR maps from 9 patients were assigned a z-score according to the mean and SD of the corresponding voxel of the atlas. The z-scores were color coded and
  • the z-maps display of the voxel-by-voxel statistical deviation of CVR from the mean of the atlas enabled detection of reductions in CVR not apparent in CVR scans. They identified generalized, symmetrical reductions in CVR as well as quantifying the extent of abnormality in focal lesions evident on CVR maps.
  • z-maps complement CVR maps by detecting, localizing, and assessing, the deviation from normal vascular responses.
  • the present invention is directed to generating an atlas of images for non-pathological CVR response by co-registering CO2 stimulated BOLD MRI CVR maps from a healthy cohort into a standard space, and calculating the mean and SD of the CVR for each voxel.
  • Patient CVR maps were then also co-registered into standard space and each voxel scored positive or negative relative to the mean, and quantified by a z-score of the corresponding voxel in the atlas. These z-scores were then colour coded and superimposed on the patient's anatomical scan to generate a z-map.
  • the inventors determined that z-maps enhance the interpretation of BOLD MRI CVR maps and highlight brain areas where vessels may have residual reactivity above the threshold for the development of steal.
  • CVR maps and z-maps enhance the interpretation of CVR maps.
  • a standardized step C0 2 stimulus was implemented, consisting of the following sequence: a baseline PETCO2 of 40 mmHg for 60 s, step to a hypercapnia of 50 mmHg for 45 s, baseline for 90 s, hypercapnia for 120 s, and return to baseline for 60 s, all during isoxic normoxia.
  • the mean (SD) change in PETC0 2 was 9.2 (0.7) mmHg.
  • PETC0 2 data was time-shifted to the point of maximum correlation with the whole brain average BOLD signal.
  • a linear, least-squares fit of the BOLD signal data series to the PETCO2 data series i.e., CVR was then performed on a voxel-by-voxel basis. For displaying CVR maps, voxels with a correlation coefficient between -0.25 and +0-25 were eliminated before color- coding the remaining CVR values (see spectrum in Figure 3).
  • Figure 1 shows maps of the mean CVR and coefficient of variation (CV) of the reference atlas. Voxels over predominantly cortical gray matter (GM) have mean CVR of 0.20 to 0.30 % ABOLD / ⁇ mmHg whereas those over
  • GM areas had the lowest CV values, ranging between 30-40%, whereas higher CV values, between 50-60%, were found in WM.
  • the high CV values calculated at the outer margin of the brain result from the variation in CVR measured where that voxel is predominantly GM, CSF, bone, W , and blood vessels in different subjects. Similarly, venous sinuses were difficult to localize consistently.
  • CVR requires the application of a stimulus and the measurement of a response to that stimulus, both potentially adding variations to the CVR values in the atlas. Of these, we can only address the issue of variability in the stimulus, leaving the variation of response to be reflected as a characteristic of the atlas.
  • the CVR atlas represents the distribution of CVR and its variance in the human brain, as reflected in our sample. It incorporates and reflects the regional anatomical differences in the response of the BOLD signal resulting from (a) tissue factors, such as age, sex, C1 ⁇ 2 consumption, capillary density, changes in blood volume, differences in blood arrival time, and vascular response time; (b) physiologic factors such as genetic makeup, variations in diet, sleep pattern, time of day, hormonal level, physical fitness, blood pressure and blood pressure response to hypercapnia, state of mind; and (c) unknown technical and mechanical changes in the MRI system over time. These form the background "noise", from which a patient's abnormal voxels, their distribution and the extent of their deviation, must be discerned.
  • tissue factors such as age, sex, C1 ⁇ 2 consumption, capillary density, changes in blood volume, differences in blood arrival time, and vascular response time
  • physiologic factors such as genetic makeup, variations in diet, sleep pattern, time of day, hormonal
  • the subject-to-subject variability in the atlas can be minimized by targeting the atlas to a particular patient group. For example, matching age, sex, medication, and other physiologic features to the target study group (for example young men with multiple sclerosis), and reducing all technical and methodological sources of variability-would leave the disease process as the dominant source of divergence of CVR from that of the reference cohort. Z-maps to compare CVR across platforms
  • Magnetic resonance imaging was performed with a 3.0-Tesla scanner (Signa; GE Healthcare, Milwaukee, Wisconsin) and consisted of BOLD acquisitions with echo planar imaging (EPI) gradient echo (TR 2000, TE 30 ms, 3.75 x 3.75 x 5 mm voxels).
  • PETCO2 data were time-shifted to the point of maximum correlation with the whole brain average BOLD signal.
  • a linear, least-squares fit of the BOLD signal data series to the PETCO2 data series was then performed on a voxel-by- voxel basis.
  • the slope of the relation between the BOLD signal and the PETCO2 was color-coded to a spectrum of colors corresponding to the direction (positive or negative) and the magnitude of the correlation to create CVR maps. Voxels with correlation coefficients between -0.25 to +0.25 were thresholded out of the maps.
  • Analytical processing software (SP 5; Wellcome Department of Imaging Neuroscience, University College, London, UK; http://www.fil.ion.ucl.ac.uk/ spm/software/spmS), was used to co-register each of the healthy individual cohort brain volumes into MNl (Montreal Neurologic Institute) standard space using a 12-parameter (Ashburner and Friston, 1997) affine transformation followed by nonlinear deformations to warp the brain volume of interest into an MNl template of identical weighting contrast.
  • the T1-weighted FSPGR volume was used to estimate the transformation normalization into standard space, as defined by a T1-weighted MNI152 standard template (Ashburner and Friston, 1999).
  • a spatial smoothing of FWHM 5mm was applied to each.
  • the mean CVR (r) and associated standard deviation ( ⁇ ( ) was calculated for each voxel (AFNI software (Cox, 1996)).
  • ID-atlas Construction of the ID-atlas proceed as described for the normal atlas except that in this case we first calculated a difference CVR map from the two time points in each of the 12 subjects. Then from the difference maps, we calculated a difference mean, and associated standard deviation for each voxel to produce the test-retest difference probability atlas (ID-atlas).
  • the spatial CVR information was further analyzed by comparing the direction and magnitude of the change in BOLD signal of each voxel to that of the corresponding voxel in the atlas; the resulting map was called a z-map.
  • This comparison consisted of three steps. First, a spatial normalization of the patient anatomical and CVR scan (Ashburner and Friston, 1999) using a MNI152 SPM distributed template supplied by the Montreal Neurological Institute was produced.
  • SD standard deviations
  • CVR differences over time were calculated for two patients who underwent more than one CVR study in a year time span (ID z-maps).
  • Z-scores were calculated voxel-by-voxel by comparing the difference CVR map of the patient to the temporal atlas. This allowed us to evaluated changes over time that differed significantly from changes over time found in a normal cohort.
  • Figure 9 presents the results of a Bland-Altman analysis comparing the CVR values for gray and white matter obtained on the different days.
  • the mean difference between days for gray matter was 0.0013 (A%BOLDSignal/AmmHg), with limits of agreement of -0.0674 and 0.0700 ( ⁇ 1.96 SD).
  • the mean difference between days for white matter was 0.0078 (A%BOLDSignal/AmmHg) with - 0.0449 and 0.0605 ( ⁇ 1.96 SD) limits of agreement.
  • Figure 10 represents the application of our sample ID atlas to assess the changes in CVR over time in a normal subject not included in the ID atlas. We can see that the majority of difference between day 1 and day 2 in the healthy subject ⁇ 1.0 SD as expected.
  • Figure 1 represents an example of the application in a patient from our database.
  • the patient was a 38 year old female who was diagnosed with bilateral moya moya and had a right EC-IC bypass.
  • a CVR was preformed both pre- and post-surgery.
  • CVR pre-surgery (Figure 11A) displays severe right side impairment with decreased CVR in the left MCA territory.
  • Post-surgery CVR suggests that the bypass on the right side reversed the steal and improved the flow, resulting in steal from the left MCA territory.
  • the z-rnaps provide additional information, suggesting that the areas of impaired CVR on the left have in fact improved after surgery when compared to a normal cohort.
  • the ID atlas was then applied to determine whether the z-map changes could be due to variability in the testing over time rather than the intervention ( Figure 11 B).
  • the ID z-maps confirmed, and gave an indication of the extent and distribution of, changes in CVR.
  • Identifying pathophysiology and distinguishing changes over time is capable of determining the voxelwise probability of a true, clinical interval change in CVR between two scans.
  • the above described z-maps consisted of a database of voxelwise mean and standard deviation of CVR suitable for identifying the probabilities and extent of abnormality of CVR. Z-maps can be thresholded to alter the balance of sensitivity and specificity in identifying abnormal voxels.
  • Identifying significant changes in a single subject as the voxel statistic does not depend on when the scan is performed, and thus includes the test to test variability.
  • the range of thresholds from 0.5 to 2.0 would provide a range of high sensitivity, low specificity to high specificity, low sensitivity.
  • ID z maps provide a confidence interval for identifying changes outside those attributable to technical and physiologic (day-to-day physiology or vasodilator/ stimulus) signal changes.

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Abstract

L'invention concerne l'interprétation et l'évaluation d'images de réactivité cérébrovasculaire (CVR), qui reposent sur un examen qualitatif d'anomalies possibles qui sont considérées comme des défauts d'homogénéité des cartes CVR qui semblent différer des cartes CVR d'individus sains. Un système d'imagerie, qui combine des cartes z avec un stimulus standardisé, offre une image à haute résolution indiquant la présence, la localisation et la gravité de la CVR pathologique. Le stimulus standardisé est sous la forme de pressions partielles artérielles ciblées de dioxyde de carbone, qui permettent d'évaluer la gravité et la distribution d'une anomalie ou la réduction d'une réponse vasculaire d'un sujet à un stimulus vasoactif dans au moins une région d'intérêt du cerveau du sujet. Des cartes Z sont utiles pour réduire les effets de variabilité de test-à-test, sujet-à-sujet et plate-forme-à-plate-forme en vue d'une comparaison d'images CVR.
PCT/CA2015/000274 2014-04-25 2015-04-27 Anomalies d'imagerie dans une réponse vasculaire Ceased WO2015161363A1 (fr)

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US15/332,567 US11880989B2 (en) 2014-04-25 2016-10-24 Imaging abnormalities in vascular response
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CN107680111A (zh) * 2017-09-21 2018-02-09 燕山大学 一种基于灰度图像的加工区域提取方法
US20220147756A1 (en) * 2019-02-19 2022-05-12 King Abdullah University Of Science And Technology Reduced feature generation for signal classification based on position weight matrix
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