Assessment of acetazolamide-enhanced arterial spin labeling MR-perfusion for

cerebral steno-occlusive diseases

Tomura N,1 ， Fujishima M1 ， Kokubun M 2 ， Kokubun M2 ， Maruyama I4 ， Watanabe Z3

Southern Tohoku Research Institute for NeuroscienceSouthern Tohoku General Hospital 　

Depart. Neuroradiology1 ， Radiology2 ，Neurosurgery3 ， GE Healthcare4

☑ The author has no conflict of interest to disclose with respect to this presentation.

　 Cerebrovascular reserve (CVR) of the brain has been studied using positron emission tomography (PET)1 using 15O, single photon emission computed tomography (SPECT) using iodine-123-N-isopropyl-p-iodoamphetamine (123I-IMP)2,3, technetium-99m hexamethyl propylene amine oxine (99mTc-HMPAO)4,5, technetium-99m ethylcysteinate dimmer (99mTc-ECD)6, xenon-133 (133Xe)6, stable xenon CT8, CT-perfusion9, MR-perfusion10, 11-13, and Doppler ultrasonography14. Acetazolamide (ACZ) is known to increase cerebral blood flow (CBF) rapidly by causing dilatation of cerebral vessels. ACZ-enhanced perfusion SPECT (ACZ-SPECT) can demonstrate areas of decreased CVR as areas of decreased ACZ reactivity2-6.

Introduction

CBF and CO2

• Carbon dioxide causes cerebral vasodilatation. As the arterial tension of CO2 rises, CBF increases.

Arterial PCO2Acetazolamide inhibits carbonic anhydrase, and it enhances tissue acidosis to cause increased CBF.

Introduction

Introduction　 Previous authors7,15,16 reported that ACZ-SPECT could predict

prognosis in patients with steno-occlusive lesion of the internal

carotid artery (ICA) and middle cerebral artery (MCA). Previous

reports using MR perfusion has used contrast materials. Recent

developed arterial spin-labeling perfusion MRI (ASL-MRI) does

not require contrast materials. The purpose of the present study is

to determine the relation between change in cerebral blood flow

(%CBF) evaluated using ACZ-SPECT with 123I-IMP and %CBF

evaluated using ACZ-challenge ASL-MRI (ACZ-ASL) in patients

with major cerebral artery steno-occlusive disease.

Patients

• Oct. 2012 ～， 14 cases (10 ～ 77 y.o. 9 males, 5

females)

• Stenosis of the unilateral ICA 6

• Stenosis of the bilateral ICA 1

• Stenosis of the unilateral MCA 1

• Occlusion of the unilateral MCA trunk 1

• Occlusion of the unilateral common carotid a. 1

• Moyamoya disease 4

Materials & Methods• ACZ-ASL:

　 MRI was performed with a 3T-MRI unit. Fast spoiled gradient-recalled

acquisition in the steady state (FSPGR) images were obtained before ASL

sequences. Pulsed continuous ASL was performed before administration

of ACZ, and 5 min., 10 min. and 15 min. after intravenous administration

of 17 mg / kg of ACZ. The ASL parameters were: repetition time (TR),

5216 ms; echo time (TE), 9.8 ms; points × arms, 512 × 8; post-labeling

delay, 2525 ms; field of view, 24 cm; number of excitation, 2; acquisition

time, 3 min 39 s.

Materials & Methods• ACZ-SPECT:

SPECT using 123I-IMP before and after ACZ administration was performed

according to QSPECT method (one day method) (Fig. 1, Iida H, et al.).

The protocols of this method are summarized; 2 dynamic scans were

acquired in quick succession with a 2-min interval between the scans. The

first scan covered the initial 0- to 28-min period, and the second was

acquired from 30 to 58 min. At 4 min per frame, 7 frames covered each of

the 2 dynamic scan periods. 123I-IMP was infused twice over1 min into the

antecubital vein at 0 and 30 min. ACZ (17 mg/kg, 1,000 mg maximum)

was administered intravenously at 20 min after the first 123I-IMP injection,

corresponding to 10 min before the second 123I-IMP injection.

Materials & Method

Diamox-SPECT: quantitative SPECT dual-table autoradiographic

Method (Q-SPECT) (Iida H, et al. J Nucl Med 2010:51:1624)

SPECT Data acquisition123I-IMP: 334MBqDiamox : 17mg/kg

IMP IMPBlood sampling

Dynamic SPECT Dynamic SPECT

Fig. 1

Materials & Methods

ASL processing steps (Fig. 2):1. 4-phase (pre and post ACZ intravenous administration) M0 images were

rigidly (6 degrees of freedom (DOFs)) registered to their averaged image using a block matching approach (Ourselin et al.18,19) implemented in NiftyReg (http://sourceforge. net/projects/niftyreg/).

2. The averaged M0 image was affinely (12 DOFs) aligned to the 3D-SPGR image.

3. The SPGR image was aligned to the SRI24 SPGR template (Rohlfing et al.20) using initial 12 DOFs affine registration followed by non-rigid registration using a fast free-form deformation (Modat et al.21) in NiftyReg.

4. The 4-phase ASL-CBF maps were computed and warped to the SRI24 template space using the transformations computed in 1–3.

Materials & Methods5. The ASL-%CBF maps were calculated as

(CBFpost – CBFpre) / CBFpre 100 (%)

where CBFpre and CBFpost denote pre-intravenous administration of ACZ

and each phase of post- intravenous administration, respectively. The

ASL-%CBF maps were then spatially smoothed with a Gaussian kernel

size of 6mm.

6. The vascular territory map in the SRI24 template space was generated by

editing the LBPA40 label map (Shattuck et al.22). The bilateral anterior,

middle and posterior cerebral artery territory cortical labels were created.

Mean CBF values, %CBF and their standard deviations were extracted

using the vascular territory map.

Materials & Methods123I-IMP SPECT processing steps (Fig. 2):

1. Pre and post acetazolamide intravenous administration 123I-IMP SPECT

CBF images were rigidly aligned to their averaged image by NiftyReg.

2. The averaged image was affinely (12 DOFs) and then non-rigidly

registered to the SPM8 SPECT template

(http://www.fil.ion.ucl.ac.uk/spm/software/spm8/) that had been warped

to the SRI24 template space.

3. The pre and post acetazolamide IMP-SPECT CBF images were warped

to the SRI24 template space using the transformations estimated in 1–2.

4. The IMP-%CBF maps were calculated by the same equation of the

ASL-%CBF map computation and spatially smoothed with a Gaussian

kernel size of 6-mm.

%CBF (0-5 min)

Vascular territory

ASL-CBF (pre)0 100(ml / 100 g / min)

ASL-CBF (post 5 min)0 100(ml / 100 g / min)

ASL-CBF (post 10 min)0 100(ml / 100 g / min)

ASL-CBF (post 15 min)0 100(ml / 100 g / min)

0 30

0 60

0 60

%CBF (0-10 min)

%CBF (0-15 min)

FSPGR

%CBF0 50

IMP-CBF (pre)0 60

(ml / 100 g / min)

IMP-CBF (post)0 60

(ml / 100 g / min)

Fig. 2

Materials & Methods

Mean CBF values, %CBF and their standard deviations were

extracted using the vascular territory map. Those three data

points (%CBF) in the anterior cerebral, middle cerebral, and

posterior cerebral arterial territory) per subject were included

in the analysis. The relation between %CBF evaluated using

the two techniques was evaluated using simple linear

regression.

 

Results

The %CBF of ACZ-SPECT ranged from 1.6 to 66.9%. The

%CBF of ACZ-ASL ranged from 1.2 to 46.8 % at 5 min post-

ACZ administration, -29.7 to 120.5 % at 10 min post-ACZ

administration, and -36.5 to 97.9 % at 15 min post-ACZ

administration. The %CBF of ACZ-SPECT correlated with

%CBF of ACZ-ASL at 5 min post-ACZ administration (r =

0.59, p < 0.0001) (Fig. 3, 4 and 5), but not with %CBF of

ACZ-ASL at 10- (p = 0.71) (Fig. 6) or 15- (p = 0.37) (Fig. 7)

min post-ACZ administration.

%CBF (whole brain)

ACZ-SPECT ： 1.6 to 66.9%

ACZ-ASL ：

1.2 ～ 46.8% at 5 min post-ACZ: p < 0.0001

　 -29.7 ～ 120.5% at 10 min post-ACZ: p = 0.71

　 -36.5 ～ 97.9% at 15 min post-ACZ: p = 0.37

Results

r = 0.63y = 0.41x + 16.6 p < 0.01

y = 0.31x + 16.6n = 84r = 0.54p < 0.001

Results

0 10 20 30 40 50 60 70 800

5

10

15

20

25

30

35

40

45

50

ACZ-SPECT (%CBF)

AS

L 5

min

. pos

t-A

CZ

y = 0.37x + 14.6r = 0.59p < 0.0001

Fig. 3

77 y.o. ， female

rt.MCA stenosis

(CT-angiography) Fig. 4

ASL post-ACZ 5min. %CBF

ACZ-SPECT %CBF

Fig. 5

77 y.o. ， fem

alert.MCA stenosis

Fig. 6

p = 0.47

0 10 20 30 40 50 60 70 80

-40

-20

0

20

40

60

80

100

120

140

ACZ-SPECT (%CBF)

ASL

10

min

. pos

t-A

CZ

(%

CB

F)

p = 0.71

Fig. 7

p = 0.38

0 10 20 30 40 50 60 70 80

-60

-40

-20

0

20

40

60

80

100

120

ACZ-SPECT (%CBF)

ASL

15

min

. pos

t-A

CZ

(%

CB

F)

p = 0.37

Discussion

To evaluate CVR by MRI, blood oxygenation level-dependent (BOLD)

images23,24 have been used with the vasoactive stimulus such as

hypercapnia and ACZ administration. BOLD-MRI can be also easily

included in clinical examination. Although BOLD-MRI is a

semiquantitative method, ASL is a quantitative method to assess whole

brain CBF. To our literature review, there has been only one report

evaluating CVR by means of ASL. Bokkers RPH et al.25 investigated

CVR using ACZ-ASL in patients with an ICA occlusion, compared with

healthy control subjects. They found decreased CVR in the affected side

compared with that in the unaffected side as well as in controls.

However, ACZ-ASL was acquired 15 min after ACZ administration in

their study. Post-labeling delay time also differed from that in the present

study.

Discussion There have no reports to compare ASL with other modalities such as PET

and SPECT in the evaluation of CVR. QSPECT technique, developed by

Iida H et al., has well-known as a definite reliable method to evaluate

CVR using IMP-SPECT by a multicenter trial. In the present study, it

was elucidated that CVR evaluated by ACZ-ASL 5 min after ACZ

administration did correlate with CVR evaluated by QSPECT.

Assessment of CVR is an alternative to SPECT in steno-occlusive

diseases of the brain.

Conclusion

The %CBF determined using ASL 5 min after ACZ

administration correlates with %CBF determined using

ACZ-SPECT.

It can be used to evaluate cerebrovascular reserve in

patients with cerebrovascular disease.

ACZ-ASL can be an alternative to ACZ-SPECT.

References1. Imaizumi M, Kitagawa K, Oku N, et al. Clinical significance of cerebrovascular reserve in

acetazolamide challenge. Comparison with acetazolamide challenge H2O-PET and Gas-PET. Ann Nucl Med 2004; 18:369-74

2. Ogasawara K, Okuguchi T, Sasoh M, et al. Qualitative versus quantitative assessment of cerebrovascular reactivity to acetazolamide using iodine-123-N-isopropyl-p-iodoamphetamine SPECT in patients with unilateral major cerebral artery occlusive disease. AJNR 2003; 24:1090-5

3. Tomura N, Sasaki K, Kidani H, et al. Reduced perfusion reserve in leukoaraiosis demonstrated using acetazolamide challenge 123I-IMP SPECT. J Comput Assist Tomogr 2007; 31:884-7

4. Cikrit DF, Dalsing MC, Lalka SG, et al. The value of acetazolamide single photon emission computed tomography scans in the preoperative evaluation of asymptomatic critical carotid stenosis. J Vasc Surg 1999; 30:599-605

5. Cikrit DF, Dalsing MC, Harting PS, et al. Cerebral vascular reactivity assessed with acetazolamide single photon emission computed scans before and after carotid endarterectomy. Am J Surg 1997; 174:193-7

6. Kim JS, Moon DH, Kim GE, et al. Acetazolamide stress brain-perfusion SPECT predicts the need for carotid shunting during carotid endarterectomy. J Nucl Med 2000; 41:1836-41

References7. Ogasawara K, Ogawa A, Yoshimoto T. Cerebrovascular reactivity to acetazolamide and

outcome in patients with symptomatic internal carotid or middle cerebral artery occlusion. A xenon-133 single-photon emission computed tomography study. Stroke 2002; 33:1857-62

8. Webster MW, Makaroun MS, Steed DL, et al. Compromised cerebral blood flow reactivity is a predictor of stroke in patients with symptomatic carotid artery occlusive disease. J Vasc Surg 1995; 21:338-45

9. Chen A, Shyr MH, Chen TY, et al. Dynamic CT perfusion imaging with acetazolamide challenge for evaluation of patients with unilateral cerebrovascular steno-occlusive disease. AJNR 2006; 27:1876-81

10. Detre JA, Samuels OB, Alsop DC, et al. Noninvasive magnetic resonance imaging evaluation of cerebral blood flow with acetazolamide challenge in patients with cerebrovascular stenosis. J Magn Reson Imaging 1999; 10:870-5

11. Vasely A, Sasano H, Volgyesi G, et al. MRI mapping of cerebraovascular reactivity using square wave changes in end-tidal PCO2. Magn Reson Med 2001; 45:1011-13

12. Mikulis DJ, Krolczyk G, Desal H, et al. Preoperative and postoperative mapping of cerebrovascular reactivity in moyamoya disease by using blood oxygen level-dependent magnetic resonance imaging. J Neurosurg 2005; 103:347-55

References13. Mandell DM, Han JS, Poublanc J, et al. Mapping cerebrovascular reactivity using blood

oxygen level-dependent MRI in patients with arterial steno-occlusive disease. Stroke 2008; 39:2021-8

14. Schreiber SJ, Gottschalk S, Weih M, et al. Assessment of blood flow velocity and diameter of the middle cerebral artery during the acetazolamide provocation test by use of transcranial Doppler sonography and MR imaging. AJNR 2000; 21:1207-11

15. Yamamoto K, Miyata T, Momose T, et al. Reduced vascular reserve measured by stressed single photon emission computed tomography carries a high risk for stroke in patients with carotid stenosis. Int Angiol 2005; 25:385-8

16. Kuroda S, Kamiyama H, Abe H, et al. Acetazolamide test in detecting reduced cerebral perfusion reserve and predicting long-term prognosis in patients with internal carotid artery occlusion. Neurosurgery 1993; 32:912-9

17. Iida H, Nakagawara J, Hayashida K, et al. multicenter evaluation standardized protocol for rest and acetazolamide cerebral blood flow assessment using quantitative SPECT reconstruction program and split dose 123I-iodoamphetamine. J Nucl Med 2010: 51; 1624-1631

18. Ourselin S. Reconstructing a 3D structure from serial histological sections. Image Vis. Comput. 2001;19:25–31.

References19. Ourselin S. Medical Image Computing and Computer-Assisted Intervention—MICCAI

2002. 2002. Robust registration of multi-modal images: towards real-time clinical applications; pp. 140–147.

20. Rohlfing T, Zahr NM, Sullivan EV, Pfefferbaum A. The SRI24 Multi-Channel Atlas of Normal Adult Human Brain Structure. Hum Brain Mapp 2010;31:798-819

21 Modat M. Fast free-form deformation using graphics processing units. Comput. Methods Prog. Biomed. 2010;98:278–284.

22. Shattuck DW, Mirza M, Adisetiyo V, et al. Construction of a 3D probabilistic atlas of human cortical structure. Neuroimage 2008; 39: 1064-1080.

23 Lythgoe DJ, Williums SC, Cullinane M, et al. Mapping of cerebrovascular reactivity using bold magnetic resonance imaging. Magn Reson Imag 1999; 17: 495-502

24. van der Zande FH, Hofman PA, Backes WH. Mapping hypercapnia-induced cerebrovascular reactivity using BOLD MRI. Neuroradiology 2005; 47: 114-120

25. Bokkers RPH, van Osch MJP, Klijn CJM, et al. Cerebrovascular reactivity within perfusion territories in patients with an internal carotid artery occlusion. J Neurol Neurosurg Psychiatry 2011; 82: 1011-1016

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