AU2004255014B2

AU2004255014B2 - Method and system of obtaining improved data in perfusion measurements

Info

Publication number: AU2004255014B2
Application number: AU2004255014A
Authority: AU
Inventors: Qing Yang
Original assignee: Apollo Medical Imaging Technology Pty Ltd
Current assignee: Apollo Medical Imaging Technology Pty Ltd
Priority date: 2004-04-30
Filing date: 2004-06-23
Publication date: 2011-04-14
Anticipated expiration: 2024-06-23
Also published as: AU2004255014A1

Description

1 Method and System of Obtaining Improved Data in Perfusion Measurements Field of the Invention 5 This invention relates to a method and system of obtaining improved data in blood perfusion measurements, and more particularly to a method and system of deriving blood perfusion indices for a region of interest of a subject. Background to the Invention 10 The process of measuring blood flow within a body of a subject non-invasively is useful in diagnosing and treating the subject. This is particularly the case where a part of a subject or patient, such as a tissue or organ, suffers from ischaemia due for example to a stroke. Determining perfusion indices including the blood flow through such a tissue or organ can provide important information to a physician in order to 15 determine an appropriate treatment regime for the patient. A number of systems pertaining to blood flow information have been disclosed. In general, the systems involve a contrast agent delivered as an intravascular bolus during a dynamic imaging session such as computerized tomography (CT), nuclear medicine (NM) or magnetic resonance imaging (MRI). The temporal profile of the 20 image intensity in a pixel or region of interest (ROI) reflects the characteristics of the contrast agent hence the blood passing through the vasculature. The typical method of obtaining quantitative perfusion indices involves several steps including: (a) convert the signal intensity profile to the contrast concentration profile depending on the type of imaging modality; (b) measure the arterial input function (AIF) from a feeding vessel to 25 the tissue of interest; (c) measure the tissue profile; (d) extract the tissue impulse residue function (IRF) from the AIF and tissue profile using deconvolution; (e) calculate quantitative perfusion indices including blood flow (BF), blood volume (BV) and mean transit time (MTT) using the IRF. Furthermore, the tissue IRF contains information about the flow heterogeneity associated with dispersion of blood transit 30 time through capillaries, which is an important factor determining the efficacy of oxygen delivery to tissue. However, in the case of major vessel disease, such as acute stroke or carotid artery stenosis, the measured AIF is often associated with a delay and dispersion before it reaches the tissue of interest, and causing overestimation of the MTT and underestimation of the BF. 35 In United States Patent No. 5,190,744 a contrast agent is injected into a patient for the purpose of detecting blood flow abnormalities. This disclosure describes in 2 some detail the different types of agents that can be used and the administration of those agents into the patient. However results of the perfusion process may not be evaluated until some time after the initial injection of the contrast agent and is thus not a real time process. Furthermore there is no disclosure of obtaining quantitative data 5 relating to blood flow and blood volume which can assist a physician to make a relatively quick and accurate diagnosis and decide on what steps can be taken to treat the patient. More particularly this document does not account for any delay or dispersion of the contrast agent in an initial bolus injection. In US Patent No. 6,542,769 there is disclosed an imaging system associated with 10 MRI whereby a bolus containing optical and MRI contrast agents is administered to a patient in order to determine perfusion indices. It uses an optical contrast agent which is injected into the patient and is used to define the arterial input function. The optical contrast is injected so as to overcome the problem of the signal intensity of the vasculature not being proportional to the amount of contrast agent with MRI. A 15 disadvantage of measuring the signal change in arteries using MRI is that it does not provide a true indication of the contrast volume as MRI depends upon electromagnetic fields that are altered due to the contrast agent. By using an optical contrast agent the invention disclosed in this document tries to overcome these disadvantages. Again there is no taking into the account the delay and dispersion associated with the bolus 20 progressing through the artery selected and through the tissue or organ in the region of interest. The present invention seeks to substantially overcome, or at least ameliorate, any one or more of the abovementioned disadvantages. 25 Summary of the Invention According to a first aspect of the invention there is provided a method of deriving blood perfusion indices for a region of interest (ROI) of a subject, the method comprising the steps of: administering a contrast agent to the subject during a dynamic imaging scan: 30 converting signal intensity data from raw images of the scan into contrast agent concentration data; deriving parameters from the contrast agent concentration data using at least one transport function that accounts for delay and dispersion of the contrast agent; and calculating the blood perfusion indices from the derived parameters. 35 The transport function may represent a probability distribution function of transit times of the contrast agent through the subject. More particularly, the method 3 may further comprise using a first model to represent an arterial transport function ha(t) through a vessel leading to the ROI, and using a second model to represent a tissue transport function hs(t) through the ROI. The transport function preferably accounts for the delay and dispersion of the contrast agent simultaneously. 5 The method may further comprise selecting an arterial input function AIFa(t) in the vessel, preferably an artery, leading to the ROI by searching pixels taken of the contrast agent concentration data. The method may further comprise measuring the contrast agent concentration C(t) remaining in the ROI. 10 The method may further comprise representing ha(t) using a gamma-variate function (GVF) in the first model such that: - ( t - tj )"' e -(' " (t ! t, Al ha, (t) = 0 (t < t) 15 where A, = a"' F(1+a ), F (a ) f x a e x dx is the Gamma function, ti is the time taken for the contrast agent to move from the initial measurement of AIFa(t) to a vessel, preferably an artery, at the entry to the ROI, ai and ai are related to the mean transit time and dispersion of ha(t). The method may further comprise estimating ha(t) after deriving values for 20 parameters ti and a, and setting a, =0 through the equation: - e-'' " (t ! ti) ha(t) = 0 (t < ti) The method may further comprise determining an estimate for the arterial input function AIFt(t) of the vessel at the entry to the ROI through the equation: AIF(t) = AIFa (t) 5 ha(t) = IF (r )h,(t - r ) d r 25 4 The method may further comprise determining an estimate of blood flow Ft and an estimate of the tissue IRF Re(t) from the deconvolution of: C(t) = (Ft/ k) AIF(t) & Re(t) 5 where kH=(1-Ha)/(1-Ht) is a correction constant taking into account different values of arterial hematocrit Ha and tissue hematocrit Ht since the contrast agent remains in the extracellular fraction of blood (plasma). The hematocrit is the volume fraction of cells in the blood, which has a typical value of Ha ~ 0.45 for large vessels such as the artery and a value of Ht 0.25 for small vessels such capillaries in tissue. 10 The method may further comprise determining an estimate for the tissue transport function he(t) from the estimated Re(t) using: he(t) d- Re(t) dt The method may further comprise determining a rise time and a mean transit 15 time of he(t) in order to determine values of parameters a 2 and a by assuming t 2 =0, or determining a peak height and a mean transit time of he(t) in order to determine values of parameters G2 and t 2 by assuming a 2 =0, where a2, 02 and t 2 are parameters related to the mean transit time and dispersion of he(t). The method may further comprise representing a simulated transport function 20 hs(t) using a GVF in the second model such that: (t - t 2 )"2 e ('t'2 '2 (t t 2 )

A

2 h,(t) = 0 (t < t 2 ) where A 2 = 0

.

2 1(1 + a 2 ), t 2 , 02 and a 2 are parameters related to the mean transit time and dispersion of hs(t) through the ROI. 25 The method may further comprise estimating hs(t) using the derived values for parameters a 2 and 02 by setting t 2 =0 through the equation: 1 h, (t)= -t2e''C2 (t 0)

A

2 5 or using the derived values for parameters G2 and t 2 by setting a 2 =0 through the equation:

--

e-(t-' 2 "2 (t > t 2 ) a 2 h,(t ) = 0 (t < t 2 ) The method may further comprise determining a simulated tissue IRF Rs(t) by: 5 R,(t)=1- fh,(r)d-r The method may further comprise determining a simulated contrast agent concentration Cs(t) as: Cs (t) = (Ft /ki) A IFt(t) ORs (t) 10 The method may further comprise fitting the simulated C(t) to C(t) using a least squares method according to: S (C(t) The method may further comprise the step of optimising the parameters Ft, t 1 , ai, aI, 02, a2 and t 2 by minimizing S iteratively. 15 The method may further reduce the number of adjustable parameters by fixing a1=0 and t 2 =0, or fixing a 1 =0 and a 2 =0 leading to five adjustable parameters. The method may further reduce the number of adjustable parameters by fixing a relative dispersion, p1= 1 i/(a 1 +t 1 ), of ha(t) resulting in a1 dependent on t 1 , hence leading to four adjustable parameters. 20 The method may further comprise calculating quantitative blood perfusion indices from the optimized parameters of Ft, ti, ai, al, 02, a 2 and t 2 . The perfusion indices may include any one or more of blood flow, blood volume, mean transit time, arterial delay time, arterial dispersion time or relative arterial dispersion, tissue dispersion time or relative tissue dispersion. 25 Preferably the ROI is a tissue. The ROI may be a pixel or a plurality of pixels in a tissue. The scan may be any one of CT, MRI or NM. In the brain, many cerebral arteries are small subjecting to partial voluming. The method may further comprise determining a venous input function (VIFa(t)) from a draining vein to estimate an AIFa(t) where a selected artery has partial voluming, the 30 vein being larger than the artery.

6 The method may further comprise the step of determining the profile of a venous input function (VIFa(t)) from a large draining vein. The AIFa(t) may then be scaled up to have the same first-pass bolus peak area as the VIFa(t) to minimize partial voluming (PV) effect from the AIFa(t). The first-pass AIFa(t) and VIFa(t) profiles can 5 be obtained by fitting the profiles to gamma-variate function (GVF) profiles respectively to remove contrast recirculation effects. The method may further comprise determining a simulated tissue IRF Rs(t) in the case that the contrast agent does not always remain in the vascular system, such as in a tumour in the subject in order to determine blood perfusion indices and 10 permeability indices using: R, (t) =1- j/h, (r)dr + Ee-k' Ih , ( i-)ek'dr (t ( t - " e' ) (t > t 2 )

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2 where h, (t) = 0 (t<t 2 ) E is the extraction fraction of the tracer in the blood stream that leaks out of the vessel 15 into tissue, and the tracer clearance rate constant k=E*Ft /Ve is a rate constant at which the leaked contrast agent diffuses back into the blood stream and leaves the tissue, Ve is volume fraction of the extravascular and extracellular space (EES). The permeability surface area product PS can be determined by PS = - F, In( 1 - E) . The method may further comprise the step of repeating the entire process 20 (except for selecting the AIF and/or VIF) on a pixel-by-pixel basis to produce quantitative maps of the perfusion indices for further analysis and presentation. According to a second aspect of the invention there is provided computer program means for deriving blood perfusion indices for a region of interest (ROI) of a subject by directing a processor to: 25 retrieve raw image data from a dynamic imaging scan of the subject after a contrast agent is administered to the subject; convert signal intensity data included in the retrieved raw image data into contrast agent concentration data; derive parameters from the contrast agent concentration data using at least one 30 transport function that accounts for delay and dispersion of the contrast agent; and calculate the blood perfusion indices from the derived parameters.

7 The computer program means may further direct the processor to select an arterial input function AIFa(t) in the vessel, preferably an artery, leading to the ROI by searching pixels taken of the contrast agent concentration data. An optimal AIFa(t) may be selected on the basis of early arrival and high and narrow peak for the arterial 5 input function. The program means may further direct the processor to measure the contrast agent concentration C(t) remaining in the ROI. The program means may further direct the processor to estimate the arterial transport function through a vessel leading to the ROI, ha(t), using a GVF in a first 10 model such that: ha(t - t)"l e '" (t t,) hk( ) =. 0 (t < ti and thereafter estimating ha(t) after deriving values for parameters ti and 0i and setting al =0 through the equation: - e '-' " (t 2! ti) 15 h,(t)= 0 (t < ti) The program means may further direct the processor to determine an estimate for the arterial input function AIFt(t) of the vessel at the entry to the ROI through the equation: 20 A IFt (t) = A IFa, (t) 0 ha,(t) where 0 is the convolution operator. The program means may further direct the processor to determine an estimate of blood flow Ft and an estimate of the tissue IRF Re(t) from the deconvolution of: 25 C (t) = (Ft /kH) A IF, (t) 0 R.e (t) where kH=(1-Ha)/(1-Ht) is a correction constant taking into account different values of arterial hematocrit Ha and tissue hematocrit Ht since the contrast agent remains in the 8 extracellular fraction of blood (plasma). The hematocrit is the volume fraction of cells in the blood, which has a typical value of Ha ~ 0.45 for large vessels such as the artery and a value of Ht 0.25 for small vessels such capillaries in tissue. The program means may further direct the processor to determine an estimate 5 for the tissue transport function he(t) from the estimate Re(t) using: he(t) -d Re(t) dt The program means may further direct the processor to determine a rise time and a mean transit time of he(t) in order to determine values for parameters a 2 and 02 by 10 assuming t 2 =0, or to determine a peak height and a mean transit time of he(t) in order to determine values for parameters G2 and t 2 by assuming a 2 =0, relating to mean transit time and dispersion of he(t). The program means may further direct the processor to estimate a simulated transport function hs(t) using a GVF in a second model such that: 15 (t - t 2 )a2 e- (t-2a (t t 2 )

A

2 h,(t ) = 0 (t < t 2 ) where A2 = 0 2 21(1 + a 2 ), t 2 , 02 and a 2 are parameters related to the mean transit time and dispersion of hs(t) through the ROI. Thereafter the program means may direct the processor to estimate hs(t) using the derived values for a 2 and 02 by setting t 2 =0 20 through the equation: 1 h,(t) = Ita2 e-''" (t 0)

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2 or using the derived values for G2 and t 2 by setting a 2 =0 through the equation: e -(U-12 /12 (t 2! t2) 2 h,(t) = 0 (t < t 2 ) The program means may further direct the processor to determine a simulated 25 tissue IRF Rs(t) by: R,(t) =1- f h,(-r)dr 9 The program means may further direct the processor to determine a simulated contrast agent concentration C(t) as: C,(t) = (Ft /kH) AIFt(t) OR,(t) 5 The program means may further direct the processor to fit the simulated C(t) to C(t) using a least squares method according to: S (C(t)-C,(t))2 The program means may further direct the processor to optimize the values Ft, ti, 01, a 1 , 02, a 2 and t 2 by minimizing S iteratively. 10 The program means may direct the processor to reduce the number of adjustable parameters by fixing a1=0 and t 2 =0, or fixing ai=0 and a2=0 leading to five adjustable parameters. The program means may direct the processor to further reduce the number of adjustable parameters by fixing a relative dispersion, pi=ai/(ai+ti), of ha(t) resulting in 15 ai dependent on ti, hence leading to four adjustable parameters. The program means may further direct the processor to calculate quantitative blood perfusion indices from the optimized values of parameters Ft, ti, 0i, ai, 02, a 2 and t 2 . The perfusion indices may include any one or more of blood flow, blood volume, mean transit time, arterial delay time, arterial dispersion time or relative arterial 20 dispersion, tissue dispersion time or relative tissue dispersion. Preferably the ROI is a tissue. The ROI may be a pixel or a plurality of pixels in a tissue. The scan may be any one of CT, MRI or NM. The program means may further direct the processor to determine a venous input function (VIFa(t)) from a draining vein to estimate an AIFa(t) where a selected 25 artery has partial voluming, the vein being larger than the artery. The program means may further direct the processor to determine the profile of a venous input function (VIFa(t)) from a large draining vein. The AIFa(t) may then be scaled up to have the same first-pass bolus peak area as the VIFa(t) to minimize partial voluming (PV) effect from the AIFa(t). The first-pass AIFa(t) and VIFa(t) profiles can 30 be obtained by fitting the profiles to gamma-variate function (GVF) profiles respectively to remove contrast recirculation effects. The program means may further direct the processor to determine a simulated tissue IRF Rs(t) in the case that the contrast agent does not always remain in the vascular system, such as in a tumour in a subject in order to determine blood perfusion 35 and permeability indices using: 10 R,(t) = 1- 0 h,(r)dr + Ee-' fh,(r)ek'dr (t - t 2 )a, e-(1-t)/0 (t > t 2 )

A

2 where h,(t) = 0 (t < t 2 ) 5 E is the extraction fraction of the tracer in the blood stream that leaks out of the vessel into tissue, and the tracer clearance rate constant k=E*Ft /Ve is a rate constant at which the leaked contrast agent diffuses back into the blood stream and leaves the tissue, Ve is volume fraction of the extravascular and extracellular space (EES). The program means may further direct the processor to calculate the permeability surface area product PS 10 by PS = -Fln(1 - E) . The program means may further direct the processor to repeat the entire process (except for selecting the AIF and/or VIF) on a pixel-by-pixel basis to produce quantitative maps of the perfusion indices for further analysis and presentation. According to a third aspect of the invention there is provided a system of 15 deriving blood perfusion indices for a region of interest (ROI) of a subject, the system comprising: scanning means for providing a dynamic image scan of the subject during which a contrast agent is administered to the subject; processor means linked to the scanning means for retrieving raw image data 20 from the scan; the processor means further: converting signal intensity data included in the retrieved raw image data into contrast agent concentration data; deriving parameters from the contrast agent concentration data using at least one 25 transport function that accounts for delay and dispersion of the contrast agent; and calculating the blood perfusion indices from the derived parameters. Brief Description of the Drawings Preferred embodiments of the invention will hereinafter be described, by way of 30 example only, with reference to the drawings wherein: 11 Figure 1 is a side view of the head of the subject indicating flow of the contrast agent through a region of interest, such as a tissue; Figure 2 is a block diagram showing a communications network including a number of scanners linked to a data storage system and a processing system; 5 Figure 3 shows various graphs against time at different parts of the subject's head as the contrast agent traverses the region of interest and the input artery; Figure 4 shows a plot whereby an input arterial profile for a small artery exhibiting partial voluming is scaled up based on a vein profile; and Figure 5 is a flow diagram showing steps performed by a computer program to 10 obtain values for the blood perfusion indices such as BF, BV and MTT. Detailed Description of Preferred Embodiments The present invention is particularly applicable to CT, MRI and MN imaging systems. A bolus of contrasting agents is introduced via a needle into a patient at, for 15 example, the arm of the patient. However the bolus can be input to any other part of the patient. A region of interest (ROI) may be a tissue 6 in a part of the patient's brain as shown in Fig. 1. Alternatively, the ROI may be a pixel or a plurality of pixels, where many pixels represent a calculated image to produce one or more perfusion maps. Blood circulating throughout the patient will contain the contrast agent and in 20 particular may be delivered to the tissue 6 via artery 8 and the blood flowing through the tissue 6 is returned to the heart via vein 10. Raw data and/or images collected by a scan, such as from a CT scanner 20, MRI scanner 30 or NM scanner 35 are forwarded to a data storage system 40 in the form of a Picture Archiving Communications System (PACS) in Fig. 2. A computer program operating on a processor 50, in the form of a 25 computer, is used to retrieve the various images or raw data from any one of the scanners 20, 30 or 35 or from the data storage system 40. The program then processes those images to provide an improved data set for a clinician to use, particularly in relation to perfusion indices including blood flow, blood volume, mean transit time, arterial delay time, arterial dispersion time or relative arterial dispersion, tissue 30 dispersion time or relative tissue dispersion.. The computer program need not reside on computer 50, but may reside in a console computer linked to any one of the scanners 20, 30 or 35. Alternatively the program may reside in a workstation (stand-alone or in a system) or in the PACS 40. In order to select an appropriate arterial input function, AIF, various images 35 (slices) from a scan are analysed to identify a major artery of interest. In CT the signal changes are directly proportional to the contrast agent concentration profile. However 12 in MRI a mathematical conversion is used in order to convert the measured signal time curve into contrast agent concentration profile. From the raw data retrieved, the program stored in the memory of system 50 automatically calculates the contrast concentration based on the measured signal intensities of the contrast agent. It then 5 searches all pixels to find the optimal AIF (or VIF) based on the criteria of early arrival, high and narrow peak for AIF, and later arrival, high and broad peak with maximum peak area for VIF. The program displays the searched AIF and VIF pixels on the corresponding images and plots the AIF and VIF time-curves. A user may further select a particular pixel while dynamically viewing its profile against the selected AIF 10 in order to confirm the best arterial input function. A better arterial pixel can be saved to replace or average with the saved AIF and then the user may "click" on further pixels in order to compare the further pixels with the updated AIF until the user is satisfied with the selected AIF. The selection of the best AIF may be done through different slices with the effort to minimize partial voluming (PV) where only a part of 15 the artery is contained in the pixel. Similarly, the best VIF profile can be confirmed by the user. Referring to Fig. 5, the computer program at step 100 thus retrieves raw data and/or images from any one of the scanners 20, 30, 35 or PACS 40, including the signal intensities containing information of the contrast agent. At step 102 the program 20 calculates the contrast agent concentration based on the signal intensities. It then plots the contrast agent concentration profile C(t) against time at step 104. Where the data is retrieved from an MRI scan, the signal intensities are converted mathematically to obtain C(t) at step 106. At step 108 the program searches pixels taken from the plots to find an optimal AIF (VIF) based on given criteria such as arrival times and peaks. At 25 step 110 the program displays the searched pixels of the AIF (VIF) and plots these as a function of time at step 112. The best pixel(s) to date are then stored in memory means, such as located at computer 50, at step 114. A decision is made at step 116 to determine if the optimal pixel has been found and stored, which decision can be made by the user. If an optimal pixel has not been found, the program keeps reverting to step 30 118 to find a better pixel than the pixel stored, which is subsequently stored at step 114. When an optimal pixel has been found the process moves to step 120, to be described hereinafter. The amount of contrast agent passing through the tissue 6 may then be measured by the computer program, the contrast agent concentration being represented as C(t). 35 Thus two known profiles are used by the computer program, one for the concentration of the contrast agent C(t) and the other for AIFa(t), being the arterial 13 input function in the vessel (artery) leading to the ROI, against time. By knowing these two particular profiles the tissue blood flow Ft and tissue impulse residue function (IRF), R(t), can be derived from a deconvolution of the equation C(t)=(F/k) AIFa(t)OR(t), where kH=(1-Ha)/(1-Ht) is a correction constant taking into account 5 different values of arterial hematocrit Ha and tissue hematocrit Ht since the contrast agent remains in the extracellular fraction of blood (plasma). The hematocrit is the volume fraction of cells in the blood, which has a typical value of Ha ~ 0.45 for large vessels such as the artery and a value of H~ 0.25 for small vessels such capillaries in tissue. 10 In other words the concentration of the contrast agent is derived by a convolution of the arterial input function and the tissue IRF multiplied by the tissue blood flow. This is the case where there is no delay or dispersion so that the selected AIFa(t) from a major artery is taken to be the same as the AIFt(t) directly feeding the tissue. 15 In practice however it is difficult to measure the arterial input function at the input to different tissues of interest. This is due to the practicalities that, arteries directly feeding the tissues are usually small in size and subject to a substantial partial voluming effect. In the case of major vessel disease such as acute stroke or carotid artery stenosis, the AIF selected from a major artery is often associated with a delay 20 and dispersion before it reaches the abnormal tissue of interest. As an example reference is made to Fig. 3 where the arterial input function is measured in artery 8 resulting in the graph of Fig. 3(A). It can be seen from the graph that there is a time ta taken from injection for the contrast agent to arrive at the point where the arterial input function is measured in artery 8. It results in a narrow 'pulse' having a large amplitude. 25 Then in Fig. 3(C) there is shown the arterial input function if measured at the tissue 6 input artery designated by 60. It can be seen that the graph has dispersed somewhat or broadened, as well as involving a time delay td in traversing the smaller artery 62 where a vessel disease such as stroke or stenosis may occur. Other normal small arteries supplying different tissues may have little delay and dispersion. Therefore it is 30 practically useful to select a normal large vessel such as the internal carotid artery (ICA), middle cerebral artery (MCA), anterior cerebral artery (ACA) or posterior cerebral artery (PCA) through multiple slices in the head and neck of the patient. The transit of the contrast agent from the artery 8 through the artery or arteries 62 up to the entry point 60 of the tissue 6 is described by the vascular transport model (VTM) using 35 the delay td and an estimated dispersion parameter to derive a simulated function AIFt(t) at the tissue input artery 60. The next part of the transit of the concentration of 14 the contrast agent is described by the tissue perfusion model (TPM) where the contrast agent traverses across the tissue 6 from an input 60 to an output 64. The measured contrast concentration profile C(t) represents the contrast agent remaining in the tissue 6 as represented by the curve shown in Fig. 3(E) and the tissue blood flow Ft and 5 impulse residue function (IRF) Re(t) can be estimated using a model-free deconvolution technique such as the singular value decomposition (SVD) method. However, such deconvolution is sensitive to noise, which may produce some mathematical solutions of Re(t) but without any physiological meaning. Further, the estimated Ft and Re(t) may not be accurate due to uncertainties associated with unaccounted delay and dispersion 10 effects. It is desirable to use a constrained deconvolution process using a model derived IRF Rs(t) with a typical shape as shown in Fig. 3(D). The estimated Re(t) can be used to derive parameters for Rs(t). A simulated tissue contrast concentration curve derived using convolution as C/(t)=(F/k)AIF,(t)@Rs(t) can be fitted to the measured C(t) curve by optimizing the 15 model parameters through an iterative least square method. The gamma-variate function (GVF), represented by equation (1) below, has been generally used to describe the temporal profile of contrast during blood circulation through the vascular system. -(t - to )a e s(-1o)/" (t to ( A G V 0 (t < to) 20 In order to account for the delay and the dispersion through the artery 62 the computer program employs a first model of GVF to represent a vascular transport function as (t - t, )"' e- -('-t ' a (t ! ti A] ha(t) = (2) 0 (t < t) 25 Where A, = of"T(1+a 1 ) since J ha(t)dt =1 , 1(a) J x"-e-dx is the Gamma function, ti is the time taken for the initial AIFa(t) measured from artery 8 15 to arrive at artery 60 and a and a are related to the mean transit time and dispersion of ha(t). If setting ai=0, equation (2) becomes, ha (t) = (3) 0 (t < ti) 5 An example plot of ha(t) versus time is shown in Fig. 3(B). The value of ti can be estimated by td as the delay between C(t) in Fig. 3(E) and AIFa(t) in Fig. 3(A). Starting with an estimate of a 1 =O, the mean transit time of ha(t) is ti + 01 and a relative arterial dispersion is defined as Pi = a1 / (ti + 01) ranging from 0 to 1. A relative dispersion value of Pi = 12% is chosen based on previous measurements of dispersions typical for 10 arteries (12%), vein (30%) and whole organs (40%). Thus an initial estimate of ai can be obtained as t 1 p 1 / (1-Pi). Referring again to Fig. 5, at step 120 the computer program applies the GVF to represent ha(t) in a first model. At step 122 an estimate of ti is made from the plots of C(t) and AIFa(t). Then at step 124, the program estimates a using ti and a relative 15 dispersion value pi assuming ai=0. The process then moves to step 126. With the estimated ti, ai and a, values, the estimated ha(t) function in equation (2) can be calculated by the computer program at step 126 to describe the arterial transport by 20 A IFt (t) = A IFa,(t) 0 ha,(t) (4) where AIFt(t) is the arterial input function at the input to the tissue designated by 60, AIFa(t) is the initial AIF at artery 8 and ® is the convolution operator. The contrast concentration profile in the tissue of interest can be further 25 determined by C(t) = (F/kH) AIF(t) 0 Re(t) (5) where kH=(1 -Ha)/(1 -Ht) is a correction constant taking into account different values of arterial hematocrit Ha and tissue hematocrit Ht because the contrast agent remains in the 30 extracellular fraction of blood (plasma). The hematocrit is the volume fraction of cells in the blood, which has a typical value of Ha ~ 0.45 for large vessels such as the artery and a value of Ht 0.25 for small vessels such capillaries in tissue.

16 With measured C(t) and the model derived AIFt(t), an estimate of Ft and Re(t) can be obtained using a model-free deconvolution technique such as the singular value decomposition (SVD) method. The deconvolution is very sensitive to noise, which may produce some mathematical solutions of R, but without any physiological meaning. 5 Further, the estimated Ft and Re(t) may not be accurate due to uncertainties associated with the initial estimate of ti, ai and ai values. It is desirable to use a constrained deconvolution process using a model derived IRF with a typical shape as shown in Fig. 3(D). Again referring to Fig. 5, the computer program- stored in memory of the 10 computer 50 directs the computer at step 128 to calculate an estimate for AIFt(t) from the convolution of AIFa(t) and ha(t) in equation (4) and at step 130 to calculate an estimate for Ft and Re(t) from equation (5). A more realistic (simulated) profile of the tissue IRF can be provided by the second model of GVF, which describes the tissue transport function as 1(t - t2 )a e ( in! 2 (t ! t2

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2 15 h,(t) = (6) 0 (t < t 2 ) Where A 2 = 0 ga 2 1,(1+ a 2 ), t 2 , a 2 and a 2 are parameters related to the mean transit time and dispersion of hs(t) through the tissue. If assuming t 2 =0, equation (6) becomes 1

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2 20 Several typical characteristic parameters of hs(t) are determined as Peak rise time (RT) = G2 a 2 Mean transit time (MTT) = a2(1+ a 2 ) (7b) 25 Alternately, if assuming a 2 =0, equation (6) becomes e- (t t 2 ) 2 h,(t) = (8a) 0 (t<t 2

)

17 Several characteristic parameters of hs(t) are determined as Peak height (PH) = 1/02 Mean transit time (MTT) = t 2 +a 2 (8b) 5 The relationship between the tissue IRF R(t) and transport function h(t) is R(t)=1- h(r)dr => h(t)= dR(t) (9) dt Since h(t) is a probability density function, R(t) is a positive, decreasing function of time with a property of with R(0) = 1 as shown in Fig. 3(D). 10 From the estimated Re(t) profile deconvolved from equation (5), an estimated transport function he(t) can be derived as he(t)= - dRe(t)/dt. The peak rise time and mean transit time of he(t) can then be calculated and used to estimate a2 and a 2 using equation (7b ) or to estimate 02 and t 2 using equation (8b) respectively. Knowing the estimates of a2 and a 2 with t 2 =0, or knowing 02 and t 2 with 15 a 2 =0, these are then input to equation (6) to determine a simulated transport function hs(t). The simulated tissue IRF Rs(t) can then be determined from equation (9) as below: R,(t)=1I- fh, (r)dr- (10) Once Rs(t) is determined, then the simulated concentration curve can be 20 determined as follows: Cs(t) =(F/k) A IF, (t) ORs(t) = (F/kg) f A IF (r) R,(t -r i)d-r (11) Using the computer program, the user selects the initial AIF and VIF, the program will automatically derive the AIFt(t) input to the tissue 6 based on the first model and the convolution thereof. Secondly the program will estimate tissue blood 25 flow Ft and IRF Re(t) and derive parameter values used to build the simulated tissue IRF Rs(t) in the second model. The program further calculates a simulated contrast curve at the tissue of interest. The seven parameters Ft, ti, 0i, ai, 02, a12 and t 2 are optimized through a least squares method in order to fit the simulated Cs(t) to the measured tissue curve C(t). A least squares fit can be represented by a minimization 30 process of the quantity S defined in equation (12) below: S= (C(t)-C,(t)) 2 (12) 18 With the optimized seven parameters F, tI, CI, al, G2, a 2 and t 2 , several quantitative perfusion indices can be determined as Blood Flow (BF) = Ft 5 Mean Transit Time (MTT) = t 2 + a2(1+ a 2 ) Blood Volume (BV) = BF*MTT (13) Arterial Delay Time (DT) = ti +ai(+ai) Arterial Dispersion Time (ADT) = ai 1+ a, Tissue Dispersion Time (TDT)= 02 1+ a 2 10 Relative Arterial Dispersion (RAD) = ADT / DT Relative Tissue Dispersion (RTD) = TDT / MTT These indices can be determined on a pixel-by-pixel basis to produce quantitative perfusion maps respectively for further analysis and interpretation. 15 This provides more accurate information to a clinician so that the clinician can decide on appropriate therapy for the patient on retrieving the above results or data. Thus referring again to Fig. 5, at step 132 an estimate of the transport function across the ROI is calculated by the computer program using the equation d he(t) = - - Re(t). At step 134 the program derives t 2 , 02 and a 2 (with either a 2 =0 or 20 t 2 =0) from the he(t) curve using the equations (7b) or (8b). At step 136 hs(t) is derived by the program knowing the values for t 2 , 02 and a 2 using the second model. At step 138 Rs(t) is derived from equation (10) by the program. At step 140 Cs(t) is determined by the program using the estimates for Rs(t), AIFt(t), kH and Ft. At step 142 a least squares method is used by the program to fit C,(t) to C(t) and to optimize the 25 parameters Ft, tI, 0I, al, a2, a 2 and t 2 by minimising S in equation (12) iteratively. Finally at step 144 the program calculates values for perfusion indices such as BF, MTT and BV etc using equation (13). An artery is usually selected in the process of obtaining an arterial input function, however in the brain it is not always easy to obtain a major artery. A smaller 30 artery in the brain may be selected instead leading to partial voluming. To compensate for partial voluming, a vein that is much larger than the artery and is usually easy to identify may be used. The user and/or computer program searches for a large vein which should have minimal partial voluming effect. A smaller artery can be selected and scaled against a vein profile. Thus, a profile of a VIF from a large draining vein is 35 determined. The AIF is then scaled up to have the same first-pass bolus peak area as the 19 VIF to minimise the PV effect from the AIF. The first-pass AIF and VIF profiles can be obtained by fitting them to the GVF profiles respectively to remove contrast recirculation effects. The area under the vein profile should be the same as the arterial profile. However, this approach of using a VIFa(t) to correct for partial volume effects 5 of AIFa(t) is not applicable outside the brain as the contrast agent does not always remain within the vascular system during transit through the body. Usually in the body a large artery without partial voluming can be found on the imaging slices. Thus in Fig. 4 the AIF profile 80 of the original artery selected is shown, which is much smaller than the expected profile due to partial voluming. Therefore a vein is 10 selected and it has the VIF profile 84. Due to recirculation effects, each profile shows a local maximum 82 (on the AIF curve) and 86 (on the VIF curve). A GVF is fitted by the computer program to the VIF to obtain an estimate of the total area (BV) under the fitted VIF curve whilst eliminating the local maximum 86 and following contour 87. Then the GVF is applied by the computer program to the selected AIF to eliminate the 15 local maximum 82 and extend the profile along contour 89. The program then uses this estimate to scale up the original AIF 80 to AIF 88 to obtain an estimate of the concentration of contrast agent from the scaled up AIF 88. This approach overcomes the problem when the VIF is represented partly with a missing end portion in the data due to a shorter scanning time in order to keep to a minimum the amount of time a 20 patient has to spent being scanned by a particular scanner. It is to be noted that the use of a GVF in each of the first and second models is for relative ease of calculations. Should the full GVF be used in both the first and second models, there will be seven adjustable parameters that need to be optimized by the least square fitting process. The computer program may provide various options to 25 allow the user to fix certain parameters such as a 1 =0 and t 2 =0 (or c=0 and a 2 =0) throughout the least square fitting process, in which only five parameters Ft, 02, a 2 , ai and t, (or Ft, 02, t 2 , a, and ti) would then need to be optimized. The computer program further allows the user to fix the relative arterial dispersion si thus ai can be calculated dependent on t 1 . A fixed value of P1=12% can be chosen based on previously published 30 results. Alternately, if one can measure AIFt(t) by identifying a small artery showing a delay relative to AIFa(t), optimized a, and t values can be determined by fitting the simulated AIFt(t) from equations (3) and (4) to the measured AIFt(t). Then a relative dispersion si value can be determined and applied to all other pixels of the same 35 subjects assuming a constant relative dispersion. Thus there will be only four 20 parameters Ft, 02, a2 and ti (or Ft, 02, t 2 and t 1 ) that need to be optimized for increased robustness of the fitting process. Furthermore, one may apply the above approach to various subjects with vascular abnormalities accompanied by delay and dispersion, such as in acute stroke 5 and stenosis. Once a consistent relative dispersion value P, is determined from all the representing cases, the vascular transport function in equation (3) can be described by a single variable ti together with a constant Pi. A two-step method can be implemented to account for delay and dispersion. At first, an initial IRF Ro(t) can be derived by deconvolution of AIFa(t) from C(t) using the model-free SVD method. The delay time 10 ti can be determined by the maximum position of Ro(t), i.e. Romax = Ro(t-ti). The t, value determined this way is less sensitive to curve noise because the deconvolution involves all data points of the time curve. In the second step, the AIFt(t) feeding the ROI can be derived from equation (3) with t, and the constant Pi, which determine a1. Then value of Ft and corrected IRF Re(t) can be obtained by deconvolution of the 15 model derived AIFt(t) from C(t) using the SVD method. Perfusion indices can be determined from the calculated Re(t) curve as MTT= f R,(r)dr, BF=Ft and BV=BF*MTT. This approach can be implemented via a computer program for fast processing of perfusion maps by accounting for delay and dispersion without a time consuming least-square-fitting process. 20 Alternatively, as the transport function h(t) is simply a probability distribution function of the transit times, it is possible to use other functions such as a modified Gaussian function in equation (14) below to substitute equation (1) hence to describe ha(t) and hs(t) respectively. ._-(-rI 12 (t > 0) A 25 h(t) = (14) 0 (t < 0) Where to > 0, A= 2-ir a[+ erf(t / Fa)]/2 and erf (t) =j. e - dx is the error function. Using the Gaussian function to substitute the first and second models in equations (3) and (8a) respectively, there are five parameters (Ft, 02, t 2 , ai and t 1 ) that need to be optimized through the fitting process. 30 Furthermore, the two models are not limited in scope to use in major vessel disease associated with the head of a patient, such as acute stroke or carotid artery 21 stenosis. The models can be used in any intra-vascular application and therefore can apply to different parts of a patient's body, such as the cortex of the kidneys, lungs or spleen. The models can be further extended to other cases where contrast may not 5 totally remain intravascular but leak into the tissue, such as in a tumour. For a tissue ROI with a mean transit time of -r, the tissue IRF can be described by the adiabatic approximation to the tissue homogeneity model as 1 (t r) R (t, r )=(15) Ee -k(t-r) (t > r where the first term is the intravascular component and the second term is the leakage 10 component. E is the extraction fraction of the tracer in the blood stream that leaks out of the vessel into tissue, and the tracer clearance rate constant k=E*Ft /Ve is a rate constant at which the leaked contrast agent diffuses back into the blood stream and leaves the tissue, Ve is the volume fraction of the extravascular and extracellular space (EES) in the tissue. 15 Normally there is perfusion heterogeneity associated with a distribution of transit time c of blood vessels in tissue. Such a distribution can be described by a probability density function hs(-r) such that the average tissue IRF involving leakage becomes R,(t) =1- h, (r)d-r+Ee-' h, (r)ek-dr (16) 20 where hs(-r) can be described by the GVF model of equation (1) or by a Gaussian distribution function of equation (14). The above described method for intravascular perfusion can be extended for perfusion measurements in a tumour by substituting equation (10) with (16) for the simulated C,(t) in equation (11). With two additional parameters, E and Ve (or k), the 25 method described above can be used to derive parameters for measuring both blood perfusion and permeability related indices including Ft, E and Ve. The parameters E and Ve have a value between zero and one. The program selects certain starting values of E and Ve such as E = 0.2 and Ve = 0.4, then further optimizes E and Ve together with all other adjustable parameters (e.g Ft, a2, aI, ai, t 1 , a2, and t 2 ) using the least squares 30 method of equation (12). The permeability surface area product can then be determined by PS = -F, In(1 - E), where PS = E*Ft when E << 1. It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific 22 embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

Editorial Note Case #2004255014 Due to amendments to the specification, the claims that follow this description are numbered pages 1-5.

Claims

1. A method of estimating blood perfusion indices, for a region of interest (ROI) by operating a computer program on intensity data input to a computer comprising: a. providing a contrast agent to an artery, wherein said artery is upstream from a region of interest (ROI), wherein said ROI comprises tissue; b. measuring intensity data to provide a tissue contrast agent curve C(t) in said tissue, wherein said C(t) is a known intensity profile measured against time; c. measuring an arterial input function AIFa(t) in said artery at a position that is upstream from said tissue, wherein said AIFa(t) is a known intensity profile measured against time; d. simulating a tissue input function AIFt(t) using a first model for a vascular transport function ha(t), wherein AIF, (t)= AIF (t) 0 h, (t), where 0 is the convolution operator; e. simulating a tissue contrast agent concentration curve Cs(t) using a blood flow Ft and a second model for a tissue transport function hs(t), wherein Cs(t)= (Ft/kH)AIFt(t) 0 Rs(t) and R, (t) =1 - J h, (r)dr , wherein kH is a hermocrit correction constant having a known value; f. using a least squares method to fit the said simulated Cs(t) to said measured tissue curve C(t) by optimizing the values of adjustable parameters of said first and second models; g. using a model-free deconvolution method to estimate initial values of said adjustable parameters for said least squares fitting process in order to derive optimized values of said adjustable parameters; and h. calculating perfusion indices from said optimized values of adjustable parameters.

2. A method according to claim 1 further comprising the step of a gamma-variate function 1 (GVF) for: a. representing a vasular transport function ha(t) such that: (t - ti) , -i-n " (t ! ti) Al h,(t) = 0 (t < t 1 ) wherein A 1 = al F(1+a), F(a) -- xa-le-xdx is the Gamma function, ti is a time delay for the contrast agent to move from the measurement position of said AIFa(t) to a vessel at the entry to the ROI, wherein ai and a3i are parameters related to the shape of ha(t); b. representing a tissue transport function hs(t) such that: (t - t2)"a2 e -(t-' ' a'" (t 2! t2) A2 h, (t) = 0 (t < t 2 ) wherein A 2 = o a21(1 ± a 2 ), t 2 is a minimum transit time for the contrast agent in tissue, wherein c 2 and a 2 are parameters related to the shape of hs(t).

3. A method according to claim 2 further comprising the step of using seven adjustable parameters (Ft, ti, aii, U 1 , t 2 , (2, a2) for the least squares fitting process, wherein said perfusion indices have the relations: a. blood flow (BF)= Ft; b. Mean Transit Time (MTT) = t 2 + G2(1+a2); c. Blood Volume (BV) = BF * MTT; d. Arterial Delay (DT)= ti + Gi(1+ai); e. Arterial Dispersion time (ADT) = Gi l + a,; 2 f. Tissue Dispersion Time (TDT) = G2 + a2; g. Relative Arterial Dispersion (RAD) = ADT/DT; and h. Relative Tissue Dispersion (RTD) = TDT/MTT.

4. A method according to claim 2 comprising the step of further reducing the number of adjustable parameters by fixing a1=0, U2=0 and a constant value for a relative dispersion, i=Gi/(Gi+ti), wherein Gi becomes dependent on ti, leading to four adjustable parameters (Ft, ti, t2,(32).

5. A method according to claim 4 further comprising the step of measuring an arterial input function AIFd(t) by further identifying an artery showing a time delay relative to said AIFa(t) and thereafter deconvolving AIF (t)= AIF, (t) @ h, (t) to determine values of ti and a3 1 of ha(t), wherein the constant value of Pi can be determined.

6. A method according to claim 1 further comprising the step of estimating a blood flow Ft and an impulse residue function R(t) by deconvolving the relation C(t) =(F, /kH)AIF, (t) 0 R(t) using a model-free deconvolution method, wherein the initial value of ti can be determined by the maximum position of said R(t), and thereafter determining a simulated AIFt(t) using ha(t) with said constant Pi and a1=0.

7. A method according to claim 6 further comprising the step of determining a blood flow Ft and a tissue impulse residue function Re(t) by deconvolving the relation C(t) = (F, / kH )AIF, (t) 0 R, (t) using a model-free deconvolution method, wherein the initial values of G2 and t 2 of said hs(t) are determined from he(t) =-dRe(t)/dt, wherein 1/72 is a peak height said he(t), and t 2 + G2 is a mean transit time of said he(t), wherein U2=0. 3

8. A method according to claim 1, wherein the contrast agent does not always remain inside the blood vessels but leaks into the tissue space, further comprising the step of determining leakage related permeability indices, wherein an extended tissue impulse residue function Rs(t) can be represented using an adiabatic approximation to a homogeneity model such that: R(t) =1 - I h,()dr+ Eek'I h,( c)ek'dr 0 0 wherein E is an extraction fraction of said contrast agent that leaks out of blood vessels into said tissue space, wherein k is a clearance rate at which said leaked contrast agent leaves said tissue space, wherein said k = E*Ft/Ve, wherein Ve is a volume fraction of extravascular space and extracellular space in said tissue, wherein Ft is said blood flow, wherein said E has a value between 0 and 1, wherein said Ve has a value between 0 and 1, wherein the said extended Rs(t) reduces to R, (t) =1 - f h, (r)dr when E=0.

9. A method according to claim 8 further comprising the step of using six adjustable parameters (Ft, ti, (ai, t 2 , (2, E, Ve), together with ai=O, U2=0 and a constant i, to simulate a contrast agent curve Cs(t), wherein C, (t) = (F, / k,)AIF, (t) 0 R, (t), and thereafter determing optimized values of the six adjustable parameters.

10. A method according to claim 9 further comprising the step of determining a permeability surface area product PS, wherein PS = -F, ln(l - E) .

11. A method according to claim 1 further comprising the step of using a Gaussian function as an alternative of GVF for: a. representing a vasular transport function ha(t) such that: 4 A1 h, (t) = 0 (t < ti) whereinti 0, A1=i .2.J [1+erf(ti/-1 4 Ji)]/2 and erf(t) - e- dx is the error function, ti is a time delay for the contrast agent to move from the measurement position of said AIFa(t) to a vessel at the entry to the ROI, a3 1 is related to the shape of ha(t). b. representing a tissue transport function hs(t) such that: [ e-t-t2)2222 (t t2) A 2 h, (t) = 0 (t < t2) wherein t 2 0, A2 = ±2z2[1+ erf (t2/v 2-- 2 )]/2, t 2 and 3 2 are related to the peak position and shape of hs(t).

12. The method of claim 1, wherein said intensity data is generated by administering a contrast agent to a body lumen of a body during a dynamic imaging scan, wherein said body lumen comprises an artery or a vein, wherein an image response from said contrast agent is recorded to computer data storage in a computer.

13. The method of claim 1, wherein said C(t) is a temporal concentration of said contrast agent obtained from said intensity data, wherein said intensity data comprises contrast images sequentially acquired from a region in a body, whereby said contrast agent concentration is plotted versus time.

14. The method of claim 1, wherein said AIFa(t) is scaled upward according to a venous input function (VIF), wherein said VIF is based on a measured contrast intensity profile from a vein draining from said ROI. 5