10/12/2013

1

Atle BjørnerudThe Intervention Centre, OUH

Dept. of Physics. Univ. of Oslo

atle.bjornerud@fys.uio.no

• Imaging methods:• T1- , T2 and T2* based analysis

• Dose-response

• Kinetic modeling:• One- and two-compartments

• ‘Perfusion’ and ‘Permeability’, DSC, DCE

• Arterial input function (AIF) and deconvolution

• ‘Leakage’ effects in tumor perfusion analysis

• Sequence considerations and protocol requirements

• Arterial spin labeling (ASL)

• Use of blood as endogenous contrast agent (flow)

• Contrast-enhanced imaging

• I.v. injection of gadolinium based contrast agents

• VASO (volume)

• Dynamic First-pass imaging (flow / volume)

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arteries/arterioles capillaries venules/veins

Tracer Delivery

PET: [15O]-H2O

MRI: [rfH]-H2OGd-DTPA

Efflux ofUnused Tracer

(Restricted) exchange

Brain tissue

• Tissue blood flow (perfusion, CBF)

• Tissue blood volume (CBV)

• Mean Transit Time (MTT)

• Capillary permeability (Ktrans)

• Extracellular volume (Ve, distribution volume)

CBV CBFMTT Ktrans

• Acute stroke

• CBV/CBF mismatch (MTT)

• Tumor imaging

• Contrast agent permeability analysis (DCE)

• Blood volume analysis (DSC)

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Two different kinetic models:

• I.V. effect: Central Volume Principle (flow/volume)

• E.V. leakage: Permeability analysis (Ktrans, EES, volume)

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T1-w post contrast FLAIR

CBV

CBF

•Metal ions with unpaired electrons:

→gadolinium (Gd3+)

→iron (Fe2+ /Fe3+)

→manganese (Mn2+)

•Magnetic moment of unpaired electrons is >> magnetic moment of

protons

•Dipolar magnetic interaction between electrons and water protons

Gd3

+

CH3NH

N

OHH

O

O

O

O N

N

O

NH

H3C

O

OO

Gd

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• Proton relaxation times: T1, T2, T2* [ms]

• Relaxation rates: R1, R2, R2* = 1/T1, 1/T2, 1/T2*

[1/s]

• Contrast agent relaxivity (r1,2): ability of CA to

increase relaxation rates

• R1,2=R1,20 + r1,2[C] ; r1,2 in mM-1s-1

[Gd]

R1,2

Tissue

signal

Brain

Tumour

pre-Gd

Tumour

post-Gd

TR

Post-Gd

contrast

Pre-Gd

contrast

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K2

K1

13

Gd3+

CH3N

H

N

OHH

O

O

O

O N

N

O

N

HH3C

O

O

O

Gd

Requires direct interaction between Gd-ion and water

T1 relaxation is limited by i.v. volume and rate of water exchange between i.v and

e.c. compartments

i.v e.c

H20

K2

K1

14

Requires direct interaction between Gd-ion and water

[C]

1/T

1

BV

Ktrans

1Donnahue et al. Magn Reson Med 1996

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By

Long-range effect caused by large magnetic

moment of gadolinium ion

∆χ>0

∆χ in tissue proportional to [CA] and B0 !

By

By

CA concentration

1/T

2*

BV

Kiselev VG Magn Reson Med. 2001 (46)

T2* relaxation not dependent on water

exchange: only limited by i.v. volume

17

[CA]

Mea

su

red

resp

on

se

[CA]

Me

asu

red

resp

on

se

CT MRI

T1-effect

T2*-effect

* Kiselev VG Magn Reson Med. 2001 (46)Donnahue et al. Magn Reson Med 1996 10/12/2013 18

• Non-linear relaxation effects must be considered in vivo!

• Susceptibility (χ) –> tissue magnetization:

local variations (∆χ) enhances relaxivity (T2*)

• Gd-induced T2* effects increases with ↑Bo whereas T1-effects reduces with ↑Bo

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CBV

CBF

MTT

Courtesy of Dr. Kyrre Emblem, OuH

Ktrans

Bolus injection of CA

Dynamic Suscetpibility Contrast (DSC) MRI

Dynamic Contrast Enhanced (DCE) MRI

T1-weighted

T2/T2*-weighted

DSC (T2*)DCE (T1-w)

-350

-300

-250

-200

-150

-100

-50

0

50

0 20 40 60 80 100

SI c

ha

ng

e

time (s)

DSC (T2*-w)

DCE (T1-w)

=long-range effect=short-range effect

DSC (T2*) DCE (T1-w)

-200

0

200

400

600

800

1000

1 11 21 31 41 51 61

Unaffected

tumor

-500

-400

-300

-200

-100

0

100

1 11 21 31 41 51 61 71

unaffected

tumor

• DSC assumptions:

• SI=SI0exp(-TE .∆R2*)

• [CA]=k.∆R2*

23

[CA]

∆R2*

∆R2*

SI

∆SI

∆R2

1/T1

SI

Linear range

T1 saturation

T2* effects

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• Conversion of SI change to absolute change in

1/T1 requires knowledge of baseline T1

• Different from DSC (T2*) where baseline T2* is

not required

• Two methods used for T1-calculation:

• Inversion/saturation recovery with multiple delay times

• GRE with multiple flip angles

• HOWEVER: question whether baseline T1

estimation improves accuracy...1

1 Haacke et al. Magn Reson Med 2007

Flip angle (deg)

SI VIBE: TR=2.8 msα1=2 deg ; α2=9 deg

T1-map

NB: B1-effects (errors in flip angle)

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Inversion time (TI)

SIT1-map T1-weighted:

� Better image quality (GRE vs EPI)

� More linear dose-response (?)

х Poorer CA sensitivity in brain

х Poorer temp res / coverage

х Requires baseline T1-map (?)

T2/T2*-weighted (DSC):

� Higher CA sensitivity in brain

� Higher temp resolution

� Increasing CA sensitivity with Bo

х Poorer image quality

х More geometric distortions

х Complex leakage effects (tumor CBV)

х Non-linear dose response (quantification)

Perfusion analysis

30

*Meier & Zieler. On the theory of Indicator-Dilution method for measurement of blood flow and

volume. J Appl Physiol. 1954

CBV, CBF

MTT

• CBF = tissue supply of blood [mL/100g/min]

• CBV= volume of blood in tissue [mL/100 g]

• Mean transit time (MTT) [seconds]

• Central volume principle*:

• Volume = Flow x MTT

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’ideal’ AIF = delta-function

F

Fa

CBV, CBF

AIF = Ca(t)

• The initial height of the measured

residue function directly reflects tissue perfusion!

• The normalized R(t) describes the relative fraction of the injected CA dose still remaining in tissue at

time t so that R(0)=1 and R(∞)=0

r(t)=F*R(t)

bolus injectionn of q0 of CAInjection profile determined by F(t)

Arterial input function (AIF, Ca(t))

Bolus-dispersion

h(t)

t

Ji(0)J1

o(t)

Ji(t1)J2

o(t)

t

Ji(t2) J3o(t)

h(t)

tt

By superposition:

R(t)f

C(t)

By measuring AIF... and tissue response...

We can determine R(t) and (at least in theory...) CBF:

R(t)f

CBV

CBF

MTTOstergaard et al 1996, Vonken et al 1999

Hc=hematocrit factor

• Delay or Tmax equal to time-shift of Rmax

Rmax

Tmax

Tmax

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DWI + MTT map (overlay)

DWI (b=1000)MTT Tmax

• Can be solved for R(t) using standard deconvolution methods like:• Singular value decomposition (SVD)1

• Fourier (FFT) based deconvolution2

• NOTE: For some deconvolution methods CBF estimates are sensitive to Tmax.

• Delay-insensitive deconvolution methods exist like block-circulant SVD2 or FFT-based methods3

1 Osteergaard et al. Magn Reson Med. 1996; 36(5):715-252 Wu et al. Magn Reson Med 2003; 50:164-174 3 Salluzzi M. Magn Reson Imaging. 2005 ;23(3):481-92

• AIF:

• Correct identification

• Dispersion effects

• Non-linear dose-response

• Partial volume effects

• Knowledge of tissue-specific constants

• Deconvolution of noisy data

39CBV CBF MTT Tmax

1 Mouridsen et al Magn Reson Med 2006;55(3):524-312 Caroll et al. Radiology 2003;227(2):593-6003 Bjørnerud and Emblem, JCBFB 20104 Knutsson et al JMRI 2006

• Tumor perfusion: most studies based on

normalized CBV analysis. A few studies on

quantitative analysis but with lower specificity1

• In acute stroke, Tmax may be the most sensitive

parameter2

• In longitudinal studies (e.g. treatment

response) quantitative analysis may have

merit3

• AIF determination or tissue normalization may

be required in most cases1 Law et al. Am J Neuroradiol 27:1975– 82 ; 2006 2 Christensen S et al. Stroke. 2009;40(6):2055-61; 20093 Sorensen et al . Cancer Res 72(2) 2012

• Relative: rCBV, rCBF*

• commonly used for parameters derived without

deconvolution or normalization

* Zierler. Circ Res 1965

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• Can estimate ratio of volume in two different regions (e.g. tumor vs WM)

• No need to determine AIF

• Assume similar dose-response in source and reference tissue..

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rCBV rCBF rMTTrTTP

No

AIF

With A

IF

CBV CBF MTTTmax

-500

-400

-300

-200

-100

0

100

1 11 21 31 41 51 61 71

unaffected

tumor

R(t)f

’Perfusion’ (CBF/MTT)

Time-scale: seconds

MTT = 3-10 sec

* Bakke and Bjørnerud; Proc ESMRMB 2012

capillary

T2 T1+C

Glioblastoma

nCBV

??

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400

500

600

700

800

900

1000

0 20 40 60 80

GRE-EPI (3 T)TR/TE/flip = 1200ms/30ms/60 deg

-8

-6

-4

-2

0

2

4

6

8

10

12

14

0 20 40 60 80

• EITHER:

• Attempt to minimize effect (sequence, predose)

OR

• Correct for effect

• Sequence optimization

• Correction schemes:

• Gamma variate fitting

• Pre-bolus (T1-saturation)4

• Correction algorithms1,2,3

1Weisskoff et al. Proc ISMRM 19942Quarles et al. Magn Reson Med 20053 Bjørnerud et al. JCBFM 20114 Hu et al. AJNR 2010

-10

-5

0

5

10

15

20

25

0 10 20 30 40 50 60 70 80

Average

WM

Tumor

Assumptions: i.v. T2* effect; e.v. T1-effects

1 Weisskoff et al, Proc SMRM (1994)

-10

-5

0

5

10

15

20

25

0 10 20 30 40 50 60 70 80

Average

WM

Tumor

No leakage: ∆R2*(t)≈K1.∆R2*(t)

Leakage:

-10

-5

0

5

10

15

20

25

0 20 40 60 80

• K2 is related to Permeability Surface area (PS) product.

uncorrected K2 map corrected

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• Only corrects for T1-dominant leakage

• Can be overcome by letting leakage constant

assume both positive (T2) and negative (T1) values

• Assumes MTT in tumor to be equal to MTT in

reference tissue (unaffected brain)

• Inherent limitation which will result in over-estimation of (T2-dominant) leakage and consequent under-estimation of (corrected) CBV in regions of elevated

MTT.0

100

200

300

400

500

600

0 20 40 60 80 100

GRE-EPI (1.5 T)TR/TE/flip = 1500ms/40ms/90 deg

T2-dominant

T1-dominant•Sequence parameters•Tumor type and malignancy

•CA dose•Field strength

*Bjørnerud et al. JCBFM 2011Bjørnerud et al; JCBFM (2011)

Bjørnerud et al; JCBFM (2011)

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Metastasis GBM GBM

Bjørnerud et al. JCBFM 2011

-10

-5

0

5

10

15

20

25

0 20 40 60 80

baseline >= 10 images

’tail’ >= 50 images

Grade I Grade II Grade III Grade IV

Normalised CBV (nCBV) = CBVHot

Spot / CBVRef

nCBV < ~2 : Low grade (grade I-II)

nCBV > ~2 : High grade (grade III-IV)

* Covarrubias et al, The Oncologist, 2004;9:528-537

o Differentiate tumour/ edema/ necrosis /

blood

o What is the correct reference tissue?

(WM vs GW)

o User dependence (def of hottest spot)

o Not all gliomas behave in the same way

(astrocytomas vs oligodendrogliomas)

Tumor heterogeneity analysis

Low grade High grade

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Tumor-grading with histogram-method*

*Emblem et al. In press. Radiology 2008

0,00

0,02

0,04

0,06

0,08

0,10

0,12

0,14

0,00 1,76 3,61 5,46 7,32 9,17 11,02 12,87

nCBV

Rela

tive f

req

uen

cy

Pilocytic Astrocytoma, grade I (Fig 2.A)

Diffuse Astrocytoma, grade II (Fig 2.B)

Anaplastic Astrocytoma, grade III (Fig 2.C)

Glioblastoma, grade IV (Fig 2.D)

*Emblem et al. Radiology 2008

---- hot-spot___ histogram

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2007-09-18 2008-06-12 2009-01-21 2009-03-31 2009-06-30

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2007-09-18 2008-06-12 2009-01-21 2009-03-31 2009-06-30

Post contrast T1-w + CBV maps

Permeability analysis

Fenestrated

Discontinuous & Fenestrated

Slow

FastLimited by Permeability x Surface Area (P S product)

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*Tofts et al. JMRI 1999

Ve

Vp

Ktrans

• Ktrans = Transfer constant; Flux of

CA from intravascular (iv) space to extravascular space (EES) [1/minutes] or [mL/100g/min]

• Ve = distribution volume of CA in EES [percent] or [mL/100g]

• kep=Ktrans/Ve = rate constant = Flux of CA from EES to iv space

[1/minutes] or [mL/100g/min]

• Vp=Plasma volume ; volume of plasma fraction in tissue [percent] or [mL/100g/min]

• Ktrans is generally a function of perfusion!

AIF = Ca(t)

Ct(t)

Ve

Vp

Ktrans

Ktrans

Vp

Ve

• Requires determination of AIF – usually better defined than in DSC

• Requires deconvolution but ‘better behaved’ since residue function is known (single exponential)

• Assume similar dose-response in source and reference tissue..(water exchange effects, T2*-effects)

• NB: CBV can be estimated from both one- and two-

compartment models

Ktrans Vp -200

0

200

400

600

800

1000

1 11 21 31 41 51 61

Unaffected

tumor

’Permeability’

time

Time-scale: Ktrans/Ve =minutes

Ktransexp(-t*Ktrans/Ve)

Ve

Vp

Ktrans

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

0.5

0 0.1 0.2 0.3 0.4 0.5

est

ima

ted

Ktr

an

s(1

/min

)

nominal Ktrans (1/min)

Ts=13.6 s

Ts=34 s

Ts=68 s

unity

0

0.05

0.1

0.15

0.2

0.25

0 0.1 0.2 0.3 0.4

rela

tiv

e f

req

ue

ncy

Ktrans (1/min)

Ts = 3.4 s

Ts=13.6 s

Ts=34 s

Ts=68 s

C. Larsson et al. JMRI 2012 C. Larsson et al. JMRI 2012

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*Kleppestø et al (JMRI in press)

-200

0

200

400

600

800

1000

1 11 21 31 41 51 61

Unaffected

tumor

>=10 baseline images

>= 5-10 minutes (slow leakage and SNR)

Temp res <= 10 sec

* Larsson et al. JMRI (in press)

• ‘Perfusion-MRI’ commonly used to refer to both CBF/CBV analysis (one-compartment) AND permeability analysis (two-compartment)

• CBV can be estimated from both models

• Perfusion analysis: T1-, T2- or T2*-weighted

• Permeability analysis: T1-weighted

• DSC (T2/T2*)• High CA sensitivity in brain tissue

• More sensitive to artifacts

• Complex dose-response

• DCE (T1)• Low CA sensitivity in brain tissue

• High sensitivity for extravasation

• Less artifacts

• Better AIF definition

• DSC sequence considerations:

• CA sensitivity: TE, Bo, dose, SE vs GRE-EPI

• Higher Bo lower TE or CA dose

• Capillary (T2) vs macrovessel (T2*)

sensitivity

• Leakage effects in DSC: sufficient scan-

duration for leakage corection (2 min)

• Temp res <= 1.5 sec

• DCE /T1-w) sequence consideration

• CA sensitivity: TR, TD, flip, dose, minimum TE

• Baseline T1-map

• Multi-flip

• IR/SR

• Added value in question..

• Temp resolution (incl CBV) <= 10 s

• Scan duration >= 5 minutes

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Thank you