Blood Oxygen Level–Dependent MRI of Cerebral CO2
Reactivity in Severe Carotid Stenosis and Occlusion
Sargon Ziyeh, MD; Jochen Rick; Matthias Reinhard, MD; Andreas Hetzel, MD;
Irina Mader, MD; Oliver Speck, PhD
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Background and Purpose—Impaired cerebrovascular reserve capacity (CVC) is a risk factor for ischemic events in
patients with high-grade carotid stenosis and occlusion. In this study, the CVC in response to a CO2 challenge was
evaluated with blood oxygen level– dependent (BOLD) MRI and the results compared with those of a transcranial
Doppler CO2 tests.
Methods—A T2*-weighted single-shot multigradient echo-planar imaging sequence was used to determine cerebral CO2
reactivity. T2* values were calculated for each pixel at rest and during a challenge with 7% CO2, and a reference function
was fitted to the T2* time courses. Whole-brain color-coded ⌬T2* parameter maps were calculated and visually
evaluated for regional differences. Additionally, a region-of-interest analysis was undertaken. Average values for ⌬T2*
normalized to changes in end-tidal PCO2 were calculated. Results were correlated with a transcranial Doppler CO2 tests
in 20 patients with high-grade stenosis or occlusion of the carotid artery.
Results—Color parameter maps showed areas of decreased BOLD effect within the internal carotid artery territory in 12
of 13 hemispheres with impaired CVC in transcranial Doppler CO2 test. Regional normalized ⌬T2* was highly
correlated with changes of middle cerebral artery blood flow velocity in transcranial Doppler CO2 test. Normalized ⌬T2*
was significantly reduced in hemispheres with impaired CVC in transcranial Doppler (P⬍0.0001).
Conclusions—BOLD MRI can easily be included in routine MRI exams. The technique is robust and yields diagnostic
information concerning the cerebrovascular reserve. (Stroke. 2005;36:751-756.)
Key Words: carotid stenosis 䡲 hemodynamics 䡲 magnetic resonance imaging
䡲 ultrasonography, Doppler, transcranial
H
igh-grade stenosis or occlusion of the carotid artery
(CA) may reduce perfusion pressure in the dependent
brain territory when collateral flow is insufficient. Consequently, autoregulatory vasodilatation occurs to maintain
regional cerebral blood flow (CBF) within normal limits. This
results in decreased or even exhausted cerebrovascular reserve capacity (CVC). CVC is determined by measurements
of CBF at rest and after exposure to vasodilatatory stimuli,
such as inhalation of CO2, intravenous administration of
acetazolamide, and breath holding. Decreased CVC is an
independent risk factor for ischemic events in patients with
carotid stenosis and occlusion.1,2
Blood oxygen level– dependent (BOLD) contrast MRI
relies on changes in blood oxygen saturation during repetitive
measurements. Deoxyhemoglobin is paramagnetic, and oxyhemoglobin is diamagnetic. The concentration of deoxyhemoglobin consequently affects the magnetic susceptibility
properties of blood and the transverse relaxation rate T2* of
the surrounding tissue.3 BOLD contrast is applied widely in
functional MRI.4,5 In activated brain areas, the increase in
regional CBF exceeds oxygen demands, raising blood oxygen
saturation and signal intensity on T2*-weighted images. It has
been shown that BOLD MRI can also be applied to CVC
examination.6 BOLD MRI is completely noninvasive, not
even requiring administration of intravenous contrast media.
However, the clinical usefulness of the method has not been
demonstrated until now. In this article, quantitative full-brain
BOLD MRI of CVC with optimized data acquisition and
processing is evaluated. The clinical utility is determined in
comparison with transcranial Doppler (TCD) CO2 testing.
Subjects and Methods
Patients
A total of 27 consecutive patients (11 women and 16 men) with
unilateral or bilateral severe steno-occlusive disease of the CA were
studied between April 2003 and February 2004. Mean age was 66
years (range 42 to 82).
CA disease was graded by using Doppler frequency shifts prestenotically, intrastenotically, and poststenotically in combination with
B-mode imaging.7 Details about the patients and their disease(s) are
Received July 16, 2004; final revision received December 3, 2004; accepted December 21, 2004.
From the Section of Neuroradiology (S.Z., I.M.), Neurocenter, Medical Physics (J.R., O.S.), Department of Radiology, Department of Neurology
(M.R., A.H.), University Hospital of Freiburg D-79106 Freiburg, Germany.
Correspondence to Dr Sargon Ziyeh, Section of Neuroradiology, University Hospital of Freiburg, Neurocenter Breisacher Str. 64 D-79106 Freiburg,
Germany. E-mail [email protected]
© 2005 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
DOI: 10.1161/01.STR.0000157593.03470.3d
751
752
Stroke
April 2005
Patient No./
Sex/Age
Degree of
Stenosis
R/L
Symptomatic
1/m/61
R 70 %
2/f/58
R 50%
L 99 %
Ischemia With
Restricted
Diffusion in
DWI
BOLD MRI
MRA*
CO2 TCD
TIA
NS
Normal
Normal
No
2
Normal
Abnormal left
3/m/62
R 95%
No
2
Abnormal right
Abnormal right
4/m/64
R 90%
L 50%
Ischemia right
NS
Not possible
Normal
5/f/53
R 50%
L 90%
No
NS
Not possible
Normal
6/m/81
R 99%
TIA
2
Not possible
Abnormal right
7/m/70
R 85 %
Ischemia
8/m/64
R 90 %
TIA
⫹
NS
Normal
Normal
NS
Not possible
Normal
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9/f/57
L 100 %
TIA
2
Not possible
Abnormal left
10/f/80
L 80 %
Ischemia
2
Abnormal left
Abnormal left
11/f/48
R 100%
L 90%
Bilateral ischemia
2, 2
Abnormal bilaterally
Abnormal bilaterally
12/m/70
L 100%
Ischemia
2
Normal
Normal
13/f/42
L 100%
Ischemia
NS
Abnormal left
Abnormal left
14/m/68
L 100%
TIA
2
Abnormal left
Abnormal left
15/f/67
R 80%
TIA
NS
Normal
Normal
16/m/74
R 95%
No
NS
Abnormal right
Abnormal right
17/f/71
R 90%
L 85 %
Ischemia
NS
Abnormal left
Abnormal left
18/m/73
L 80%
No
NS
Normal
Normal
19/m/68
R 80%
L 100%
TIA right
NS
Abnormal bilaterally
Abnormal bilaterally
20/f/55
R 80%
No
NS
Not possible
Normal
Normal
⫹
21/f/58
R 95%
Ischemia
2
Normal
22/m/64
L 100%
No
NS
Abnormal left
Normal
23/m/74
R 100%
L 80%
Ischemia right
2
Normal
Normal
24/m/72
R 70%
L 100%
Ischemia left
NS
Abnormal bilaterally
Abnormal bilaterally
25/f/74
R 80%
Ischemia
NS
Not possible
Normal
26/m/64
R 100%
No
NS
Normal
Normal
27/m/64
R 95%
No
NS
Normal
Normal
M indicates male; f, female; R, right; L, left; TIA, transient ischemic attack; *time-of-flight MRA of the circle of Willis; 2, significant
reduction or loss of flow-related ipsilateral MCA signal; DWI, diffusion-weighted imaging.
given in the Table. Symptomatic patients were studied at least 1
week after the last ischemic event.
Magnetic Resonance Protocol
MRI was performed on a 1.5T scanner (Sonata; Siemens). A
transversal T2-weighted fluid-attenuated inversion recovery sequence and a transversal diffusion-weighted sequence were acquired
for detection of chronic and acute infarction, respectively. In
addition, an arterial 3D time-of-flight magnetic resonance angiography (MRA) of the circle of Willis was acquired and reconstructed as
maximum intensity projections. BOLD imaging was performed with
a single-shot multigradient echo-planar imaging (EPI) sequence.8
Twenty slices were acquired in the transversal plane. Repetition time
was 3000 ms, flip angle 90°, matrix size 64⫻64, field of view
220⫻220 mm, and slice thickness 5 mm. Four echo images were
read out per measurement, with echo times of 17, 44, 71, and 98 ms,
respectively. A total of 100 measurements were acquired. During
measurements 21 through 60 (ie, during 2 minutes), room air
enriched with 7% CO2 was administered via a breathing mask
covering the nose.
Patient monitoring comprised continuous ECG recording, pulse
oximetry, and recording of inspiratory, end-tidal PCO2 (PETCO2), and
blood pressure (MAGLIFE C; Schiller).
In addition to patient examinations, 5 healthy volunteers (3 men
and 2 women; mean age 30 years) were studied with the same
protocol. In these studies, 3 different inspiratory CO2 concentrations
of 3%, 5%, and 7% CO2 were administered.
Data Analysis
Quantitative I0 and T2* values were determined pixel-wise using a
monoexponential model. The maps were motion-corrected during
Ziyeh et al
BOLD MRI of Cerebral CO2 Reactivity
753
Figure 1. T2* time course of an individual cortical pixel. Original time course (dashed line) and
result of fitting (solid line). The superimposed
gray field indicates the range of scans during
administration of 7% CO2.
Downloaded from http://stroke.ahajournals.org/ by guest on July 31, 2017
the reconstruction process.9 The T2* maps were spatially filtered
with a 3D Gaussian filter (full width at half maximum 10 mm) and
the T2* time courses were filtered with a median filter (kernel size 5).
A pixel-wise least square data fit of a model function to the T2*
time course was performed. The reference function is based on a
compartment model of CO2 diffusion between the pulmonary air
spaces and blood along the alveolar membrane and is mathematically
described as
共1兲 T*2 (t)
再
y1
⬊ 0 ⬍ t ⬍ t1
⫺共t⫺t1兲/␶1
⬊ t1 ⬍ t ⬍ t2
兲
⫽ y1⫹ydiff 䡠 共1⫺e
⫺t
y2⫹关关 y1⫹ydiff 䡠 共1⫺e⫺共t2 兲/␶1兲兴⫺y2兴 䡠 e⫺共t⫺t2兲/␶2 ⬊ t2 ⬍ t
1
where y1⫽baseline T2* before and y2⫽baseline T2* after administration of CO2, ␶1⫽time constant of exponential increase and ␶2⫽time
constant of exponential decrease of T2*, t1⫽start and t2⫽end of CO2
administration, ydiff⫽mathematical maximum increase of the
e-function. ⌬T2*⫽T2*max⫺(y1⫹y2)/2.
The rationale for the data fit is to eliminate the oscillations of T2*
to define a baseline and maximum. The T2* time course is shown for
an individual pixel together with the fitting result in Figure 1. The
variables ⌬T2*⫽T2*max⫺T2*base, ⌬R2*⫽1/ T2*base⫺1/ T2*max, and
relative ⌬T2*⫽(T2*max/T2*base)⫺1 were calculated from the fitted data
and displayed as parameter color maps. These parameter maps were
evaluated by visual inspection by an experienced neuroradiologist
(S.Z.).
Regions of interest (ROIs) for the right and left middle cerebral
artery (MCA) territory comprising all slices without susceptibility
artifacts from the skull base were manually defined on T2*-weighted
images. ROI-based averages of ⌬T2* were calculated and normalized
to the change in PETCO2 (⌬PETCO2) for better comparability with TCD
CO2 testing. The results of these ROI analyses were included in the
statistical evaluation.
For statistical analysis, each particular hemisphere was classified
as normal or decreased in CVC according to the results of TCD CO2
testing. Normal distribution was proven and a 2-tailed t test for
normalized ⌬T2* was performed. Pearson correlation coefficients for
normalized ⌬T2* and the change in normalized mean CBF velocity
(CBFV) as determined in TCD CO2 testing (⌬CBFV/⌬PETCO2) were
calculated. SPSS software was used for statistics.
TCD CO2 Testing
Measurements were performed with subjects in a supine position.
Both MCAs were insonated through the temporal bone window
using 2-MHz transducers attached to a headband (DWL-MultidopX4; Sipplingen). PETCO2 was measured continuously with an infrared
capnometer (Normocap; Datex). Baseline flow velocity was measured for 1 minute. Subsequently, a 7% CO2–air mixture was
administered until reaching stable hypercapnia, which was maintained for 60 to 90 s. The measurements were continued for 60 s until
baseline values were reached after withdrawal of CO2. The CO2
reactivity was calculated as the maximum percentage increase in
mean CBFV during hypercapnia divided by the increase in PETCO2 in
kilopascals. The determination of CO2 reactivity in the nonstenosed
or minor stenosed sides of 127 patients (66⫾9 years) with unilateral
severe carotid stenosis yielded a lower threshold of 8.25%/kPa (5%
quantile). This value was defined as the cutoff to clearly pathological
CO2 reactivity.
BOLD MRI and TCD CO2 testing were performed within several
hours to 7 days in a random sequence. Operators were blinded to the
results of the other method. Results of TCD CO2 testing were
unknown when the parameter maps were evaluated by visual
inspection. The study was approved by the local ethics committee,
and all participants gave written informed consent.
Results
Volunteer studies indicated a dependence of ⌬T2* from
inspiratory CO2 concentration (Figure 2). Color parameter
Figure 2. Dependence of ⌬T2* on inspiratory CO2 concentration
in 5 healthy volunteers. BOLD effects are most prominent in
gray matter. GM indicates gray matter; WM, white matter.
754
Stroke
April 2005
Figure 3. ⌬T2* map of patient 13 with
occlusion of the left internal CA and
exhausted CVC in TCD CO2 testing. In
the left internal CA territory, the T2*
increase is clearly diminished. Color
scale ⌬T2* in milliseconds.
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maps showed the highest BOLD response in cortical and deep
gray matter and within venous vessels with a maximum ⌬T2*
of ⬇10 to 12 ms. However, a less pronounced effect could
also be clearly demonstrated in white matter. No significant
differences between parameter maps of ⌬T2*, relative ⌬T2*,
and ⌬R2* were observed.
In the patient group, average ⌬PETCO2 was 1.75 kPa (SD
0.4). Mean heart rate and O2 saturation were 67.1/min (SD
13.2) and 94.8% (SD 1.5) during normocapnia, and 71.8/min
(SD 16.9) and 95.4% (SD 1.6) during hypercapnia. The
hypercapnia-induced average increase in mean arterial blood
pressure was 13 mm Hg (1.74 kPa).
Seven patients, all with unilateral high-grade stenosis,
could not be evaluated by TCD CO2 testing because of an
insufficient bone window.
A total of 40 hemispheres were evaluated in the patient
group with sufficient transtemporal ultrasound transmission.
Nine patients (18 hemispheres) with bilaterally normal CVC
in TCD CO2 testing showed a symmetrically distributed
normal BOLD response on color parameter maps. One patient
with occlusion of the left CA showed normal CVC in TCD
CO2 testing. The BOLD effect was clearly reduced in the left
MCA territory on ⌬T2* parameter maps.
TCD CO2 testing showed a decreased CVC in 1 hemisphere in 7 patients. In 6 of 7 affected hemispheres, BOLD
MRI demonstrated large ipsilateral areas of reduced BOLD
response (Figure 3). Visual inspection of the parameter maps
did not reveal clear abnormalities in 1 patient with unilateral
impairment of CVC in TCD CO2 testing.
Both hemispheres were affected by reduced CVC in TCD
CO2 testing in 3 patients with bilateral high-grade stenosis or
occlusion. BOLD MRI parameter maps showed a bihemispherically reduced response in the latter patients. However,
these maps were difficult to interpret because of their inhomogeneous appearance and the lack of a normal reference
hemisphere.
In the patient group, hemispheres with normal CVC in
TCD CO2 testing showed an average ⌬T2* normalized to
⌬PETCO2 of 1.8 ms/kPa (1SD 0.57). Hemispheres with impaired CVC in TCD CO2 testing showed a reduced average
normalized ⌬T2* of 0.7 ms/kPa (1SD 0.64; Figure 4a). The
patient with unilateral impairment of CVC in TCD CO2
testing and normal ⌬T2* parameter maps showed a normalized ⌬T2* of 1.9 ms/kPa on the affected and 2.1 ms/kPa on
the contralateral side. The patient with bilaterally normal
CVC in CO2 TCD CO2 testing and reduced BOLD effect in
the left MCA territory showed an ipsilateral ⌬T2* of 0.8
ms/kPa (contralateral 1.3 ms/kPa).
The difference between hemispheres with normal and
hemispheres with impaired CVC in TCD CO2 testing was
statistically highly significant (P⫽0.0001). A linear correlation between normalized ⌬T2* and ⌬CBFV in TCD CO2
testing (Figure 4b) could be clearly shown, with r⫽0.71
(P⬍0.001).
In 2 of 7 patients with absent temporal ultrasound window
color, T2* maps showed large areas with reduced BOLD
effect in the ipsilateral MCA and internal CA territory,
respectively. Quantitative ROI-based analysis revealed a low
mean normalized ⌬T2* of 1.1 and 0.3 ms/kPa in the ipsilateral
MCA territory, and 2.0 and 2.3 ms/kPa on the contralateral
side. In 5 of 7 patients, ⌬T2* parameter maps did not show
any side differences. These patients showed an average
normalized ⌬T2* of 2.1 (range 1.4 to 4.2 ms/kPa).
Inspection of arterial time-of-flight angiography revealed
absent or significantly reduced flow-related signal attributable to slow flow and saturation in the MCA of 8 of 15
hemispheres with reduced and 3 of 39 hemispheres with
normal BOLD effect, respectively.
Discussion
Various methods exist for CVC determination. In xenonenhanced computed tomography (CT), single-photon emission
Ziyeh et al
BOLD MRI of Cerebral CO2 Reactivity
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Figure 4. a, ROI-based analysis of 40 hemispheres. Means and 95% CIs of normalized ⌬T2* in hemispheres with normal and with
decreased CVC in TCD CO2 testing. t test showed a P⫽0.0001. b, Correlation of normalized ⌬T2* with CBFV increase in TCD CO2 testing. R⫽0.71; P⬍0.001.
CT10 and positron-emission tomography,11 CBF is determined
before and after administration of a vasodilatatory stimulus.
Furthermore, positron-emission tomography may demonstrate
increased oxygen extraction fraction and cerebral blood volume
in severe hemodynamic impairment.12 These methods are expensive and the subject is exposed to radiation. The completely
noninvasive evaluation of CVC with TCD CO2 testing is
presumably the most widely applied method in clinical practice.
Drawbacks of TCD CO2 testing are an insufficient temporal
bone ultrasound window in ⬇10% to 20% of the patients and
relatively low diagnostic accuracy (index of validity ⬇75%,
compared with xenon-enhanced CT13).
First attempts to determine CVC by means of BOLD MRI
date back to 1994, when changes in R2* after administration
of acetazolamide and CO2 were observed in the rat brain14
and CO2-induced signal increase in normal subjects could be
demonstrated.6 The effect was conspicuous in cortical and
deep gray matter but was not significant in cerebral white
matter.6 In 1995, first results of BOLD contrast MRI in 4
patients with unilateral CA occlusion were reported.15 In this
study, only a single slice could be acquired and evaluated by
means of simple difference images and ROI analysis of pial
veins. It could be shown that acetazolamide-induced signal
increase in pial veins was lower in patients with reduced
ipsilateral CVC. In a larger series of patients with unilateral
CA stenosis, Lythgoe et al16 found a significant correlation
between the side difference of hemispheric reactivity determined by BOLD MRI and TCD CO2 testing, respectively.
However, a significant correlation between the particular
hemispheric relative BOLD signal increase and CO2 reactivity in TCD CO2 testing could not be demonstrated.
In contrast to the study by Lythgoe et al,16 our study
demonstrated a significant correlation between normalized
⌬T2* and ⌬CBFV/⌬PETCO2 in TCD CO2 testing. This is
probably attributable in part to the enhanced sensitivity of
single-shot multigradient-echo functional MRI compared
with conventional EPI sequences.9,17,18
Because BOLD effects are small, they can best be depicted
by statistical analysis of repeated measurements. The greater
amount of acquired data may also have enhanced the sensitivity of our method. The number of measurements in our
study was 5⫻ higher than for Lythgoe et al.16 By the
acquisition of 4 different echoes, our sequence further increases the number of acquired data points by a factor of 4.
As another advantage, the method allows a calculation of
parameters with defined dimensions, such as ⌬T2* in milliseconds instead of dimensionless signal intensities. Consequently, quantitative results and comparisons can be
achieved. It could be demonstrated in healthy subjects that
⌬CBF can be calculated if baseline T2* and ⌬T2* are
available.19 This potential further development of our method
was not included in our article because the assumptions
regarding the relation of blood volume and flow (Grubb’s
exponent) are not proven to be true in our patient population.
The fit of the T2* time course is advantageous because it is
insensitive to differences in the temporal evolution of the
vascular response to CO2. It could be shown that the time
course of the BOLD signal change in response to CO2 differs
between white and gray matter. The BOLD signal rise in
white matter is much slower and sustained.20 Because the
white matter comprises approximately one third of the brain
volume,21 its contribution to hemispheric BOLD effect
should not be neglected.
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An impaired CVC may be diagnosed at first glance by use of
⌬T2* parameter maps if 1 hemisphere shows an unambiguously
reduced BOLD response. A quantitative ROI-based analysis
appears valuable in cases with bilaterally impaired CVC, and it
may increase the sensitivity and specificity of BOLD MRI in
cases with ambiguous results on solely visual inspection. However, a larger number of patients, as well as normal controls,
must be examined to establish normal values.
Inspection of ⌬T2* parameter maps and quantitative ROIbased analysis were in good agreement with TCD CO2 testing
in most cases. Results were discrepant in 2 cases. One patient
with unilateral asymptomatic CA occlusion showed a reduced
CVC in TCD CO2 testing but normal ⌬T2* parameter maps.
This might reflect the presence of sufficient blood supply via
leptomeningeal collateral arteries. In 1 patient with unilateral
asymptomatic CA occlusion, TCD CO2 testing was normal,
but BOLD MRI showed a pathological CVC. Because the
flow-related vascular signal of the ipsilateral MCA was
severely reduced, it may be speculated that results of TCD
CO2 testing were false-negative in this case.
Time-of-flight MRA may, to some degree, anticipate results
of BOLD MRI. A severely saturated flow signal indicates a
higher probability of impaired CVC. However, there are patients
with only slight reduction of flow-related signal in the ipsilateral
MCA and reduced CVC. On the other hand, hemispheres with
severely reduced or absent flow-related signal can show normal
CVC. The latter constellation may be suggestive of sufficient
leptomeningeal collateral flow.
The method presented in this article is mature and robust.
It can easily be included in a routine MRI examination and
may serve as an alternative to xenon-enhanced CT or nuclear
medicine methods in cases in which TCD CO2 testing cannot
be successfully applied. BOLD-based CVC measurements in
combination with TCD CO2 testing may even offer additional
information otherwise unavailable: a reduced CVC in TCD
CO2 testing together with a normal CVC in BOLD MRI may
be indicative of sufficient collateral blood supply to the
relevant vascular territory.
Conclusions
CVC can be determined by BOLD MRI and administration of
CO2. BOLD measurements can easily be included in clinical
MRI sessions, representing an alternative to TCD CO2 testing,
which is sometimes hampered by an insufficient bone window.
Acknowledgments
S.Z. contributed conceptual study design, execution of the study, and
writing of this manuscript; J.R. was responsible for development of data
evaluation with the data fit; M.R. contributed evaluation of transcranial
Doppler CO2 tests; A.H. was responsible for conceptual study design
and evaluation of transcranial Doppler CO2 tests; I.M. contributed data
analysis and statistics; and O.S. performed development of data evaluation with the data fit, programming of the multiecho gradient-echo
sequence, and supervision of data acquisition.
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Stroke. 2005;36:751-756; originally published online February 10, 2005;
doi: 10.1161/01.STR.0000157593.03470.3d
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