Jian Shen1, Chau Vu1, Soyoung Choi2, Aart Nederveen3, and John Wood1,4
1Biomedical Engineering, University of Southern California, Los Angeles, CA, United States, 2Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, United States, 3Academic Medical Center, Amsterdam, Netherlands, 4Division of Cardiology, Children's Hospital Los Angeles, Los Angeles, CA, United States
Synopsis
This
study demonstrated tissue oxygen extraction change in patients with sickle cell
disease after
Acetazolamide injection using Asymmetric Spin Echo technique, and
compared with global oxygen extraction change revealed by TRUST. The results
suggested that global oxygen extraction decreased as blood flow increased,
while tissue oxygen extraction remained stable. And this mismatch might be a
proof to the existence of "physiological shunting".
Introduction
Sickle cell
disease (SCD) is caused by hemoglobin mutation, causing chronic hemolytic
anemia.1,2 The quantitative analysis of cerebral oxygen extraction
fraction (OEF) is important in assessing the balance between oxygen supply and
demand for SCD. Asymmetric Spin Echo (ASE) sequence is a modified spin echo
sequence whose contrast is sensitive to R2’ and venous volume fraction,
allowing calculation of voxel-wise OEF maps, offering tissue OEF information.
Previous studies have examined relative OEF changes during prolonged inhaled
gas challenges.3 Unfortunately, these challenges can modify cerebral metabolic
rate of oxygen (CMRO2) in addition to blood flow and blood volume,
complicating their interpretation.4,5 In this study, we used
acetazolamide injection to evaluate tissue and global OEF changes in patients
with sickle cell disease. Acetazolamide (Diamox) is an exogenous vasoactive
stimulus that causes cerebral vasodilation. We hypothesized that acetazolamide
would increase non-nutritive cerebral blood flow (CBF), decreasing whole brain
OEF proportional to the changes in brain blood flow with relatively little
change in tissue OEF. Methods
Theory: ASE can be
viewed as a modification of SE in which the acquisition window is shifted in
time relative to the center of spin echo, increasing dephasing and creating signal
decay with R2’ contrast. The signal
decay can be calculated as6,7:$$S(\tau) = \rho*(1-\lambda)*f(\lambda, \delta\omega, \tau)*exp(-TE/T2)*g(\tau, T1, TR)(1)$$
where ρ is
the spin density, λ is
the venous blood volume fraction, τ is
the time shift from the expected echo formation, and δw is
the frequency shift induced by the microscopic susceptibility. In the presence
of randomly oriented cylinders containing de-oxygenated hemoglobin, δw can
be written as follows: $$\delta\omega = 4/3*\pi*\gamma*\chi*Hct*B_{0}*OEF(2)$$
where γ is
the gyro-magnetic ratio, B0 is the main magnetic field strength, Hct is the
fractional hematocrit and Δχ is
the susceptibility difference between fully oxygenated and fully deoxygenated
blood. The reversible relaxation rate, R2’, is simply the product of λ and δw. With constant TE and a sufficiently long
TR, the signal decay can be simplified to two relaxation regimes separated by :$$S_{s}(\tau) = c * exp(-0.3*\lambda*(\delta\omega*2\tau)^{2})(3)$$ $$S_{L}(\tau) = c * exp(-\lambda*\delta\omega*2\tau+\lambda)(4)$$
R2’
and λ can
be estimated calculating the slope and intercept of plot of log (SL(t))
versus 2t
(Eq 3).
MRI
acquisition:
A total of 8 patients (female 25%, age 24±4) with sickle cell disease were
studied. All subjects underwent an MR study using Philips 3T Achieva with a
32-element head coil. For each subject, ASE was acquired before and after infusing
acetazolamide (16 mg/kg over three minutes) with the following parameters: TR =
3s, TE = 62ms, resolution = 3mm * 3mm * 6mm, matrix size = 64*64, range = 10ms : 0.5ms : 20ms. Each scan was
composed of 28 dynamics, including 7 spin echo scans (τ =
0) and other 21 equally spaced τ values from 10ms to 20ms. All subjects also underwent
normal anatomical 3D T1 and T2 scans. Total brain blood flow and global
cerebral oxygenation were measured by phase contrast MRI and T2 relaxation
under spin tagging as previously described.4,8
Image
Processing:
For each subject, the ASE data were smoothed by a 3*3 Gaussian kernel. We
rigidly registered the ASE data to skull-stripped T1 image (BrainSuite), and
generated masks of gray matter and white matter using FMRIB Software Library
(FSL) Automated Segmentation Tool (FAST).9 For every voxel in ASE
dataset, the first 7 spin echo values were averaged, and the other 21 values
with different τ values were fitted linearly in log space to
generate R2’ and λ. Voxel-wise OEF maps were subsequently
derived using equation 2. Results
Typical anatomical
SE images and signal decay curves are illustrated in Figure 1, and derived OEF
maps are shown in Figure 2. Measurements of tissue OEF, global OEF, CBF and
global CMRO2 are summarized in Table 1.
Following
acetazolamide, the CBF increased significantly from 77.2 to 109.6 ml/100g/min
(p < 0.01), the global OEF (derived from TRUST) decreased from 33% to 24% (p
< 0.01), while the global CMRO2 remained stable (Figure 3). Surprisingly, the tissue OEF value in white matter and gray matter was unchanged with
acetazolamide (Figure 4). Discussion
In this study, we
replicated the expected effects of acetazolamide infusion, namely, reciprocal
changes in CBF and OEF with stable CMRO2. If the increased oxygen
delivery produced by acetazolamide were evenly distributed to perfusing
capillaries, one would expect parallel changes in tissue and global OEF
measurements. However, the absence of
any detectable decline in tissue OEF, despite a 27% reduction in global OEF,
indicates that increased blood flow is bypassing capillary networks
(non-nutritive flow), supporting the existence of recruitable arteriovenous
bypass channels. Our laboratory has postulated the existence of “physiologic
shunting” in chronically anemic subjects8 for several years
based upon the unexpectedly low OEF’s observed in both the systemic and
cerebral circulations, but the present work provides compelling evidence for
this physiology. Acknowledgements
This work is
supported by the National Heart Lung and Blood Institute (1RO1HL136484-A1,
1U01HL117718-01), the National Institutes of Health (1R01-NS074980), the National
Institute of Clinical Research Resources (UL1 TR001855-02) and by research
support in kind from Philips Healthcare.References
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