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Published online before print March 27, 2003, 10.1148/radiol.2272020903
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(Radiology 2003;227:567-574.)
© RSNA, 2003

Technical Developments

Sickle Cell Disease: Continuous Arterial Spin-labeling Perfusion MR Imaging in Children1

Kader K. Oguz, MD, Xavier Golay, PhD, Francesca B. Pizzini, MD, Catherine A. Freer, MS, Nevada Winrow, PhD, Rebecca Ichord, MD, James F. Casella, MD, Peter C. M. van Zijl, PhD and Elias R. Melhem, MD

1 From the Depts of Radiology and Radiological Sciences (K.K.O., X.G., F.B.P., N.W., P.C.M.v.Z., E.R.M.) and Pediatrics, Div of Pediatric Hematology (C.A.F., J.F.C.), Johns Hopkins Med Insts, Baltimore, Md; F. M. Kirby Research Ctr for Functional Brain Imaging, Kennedy-Krieger Inst, Baltimore, Md (K.K.O., X.G., F.B.P., P.C.M.v.Z., E.R.M.); and Dept of Pediatrics and Neurology, Children’s Hosp of Philadelphia and Univ of Pennsylvania (R.I.). Received Jul 24, 2002; revision requested Sep 26; revision received Oct 11; accepted Dec 10. Supported by NIH grant R21-0035-01. Address correspondence to E.R.M., Dept of Radiology, Hospital of the University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104 (e-mail: emelhem@rad.upen.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Cerebral blood flow (CBF) was measured with continuous arterial spin-labeling perfusion magnetic resonance (MR) imaging in 14 children with sickle cell disease and seven control subjects. Mean CBF values were higher in patients (P < .005) than in control subjects in all cerebral artery territories. Three patients had decreased CBF in right anterior and middle cerebral artery territories compared with CBF on the left, and one patient had a profound decrease in CBF in all three territories in the right hemisphere. Baseline CBF was significantly decreased in territories seen as unaffected on conventional MR images and MR angiograms in four children with sickle cell disease.

© RSNA, 2003

Index terms: Magnetic resonance (MR), in infants and children • Magnetic resonance (MR), perfusion study, 17.121416, 17.14144 • Cerebral blood vessels, flow dynamics, 173.781, 174.781, 1756.781 • Cerebral blood vessels, MR, 17.121411, 17.121413, 17.121416, 17.12142, 17.12144 • Sickle cell disease (SS, SC), 17.651


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
Materials and Methods
Results
 Discussion
 REFERENCES
 
Neurologic complications resulting from macro- and microvasculopathies are a common cause of morbidity and mortality in children with sickle cell disease (SCD) (1–5). In affected children, magnetic resonance (MR) angiography and transcranial Doppler sonography are useful for demonstrating involvement of the large cerebral vasculature (6–16), whereas MR imaging is an established method for showing both subclinical and clinical brain infarctions (17,18). Another important feature of such diagnostic methods is their ability to aid in prospective identification of affected children at risk for cerebral vascular involvement, brain injury, and, more important, cognitive decline and stroke. Study results have shown that in neurologically asymptomatic children with SCD, high velocities in the internal carotid and cerebral arteries on transcranial Doppler sonograms and subclinical brain infarcts on MR images are strong predictors of stroke (7,8,10,12,15,19) and that subclinical infarcts seen on MR images are associated with cognitive impairment (20–22).

Recently, however, Wang et al (7) demonstrated a lack of concordance between transcranial Doppler sonographic findings and the development of subclinical infarcts as seen on MR images and have advocated the use of more sensitive and specific indicators of early brain injury. To that end, imaging of regional cerebral blood flow (CBF), oxygen extraction, and oxygen and glucose consumption by using positron-emission tomography (PET), xenon-enhanced computed tomography (CT), and gadolinium-enhanced perfusion MR imaging have shown promise as more sensitive indicators of regional abnormalities in children in whom transcranial Doppler sonographic and MR imaging findings are normal (5,23–29). However, the application of these techniques in asymptomatic children with SCD has been limited by the need for exogenous contrast material, elaborate setups, or high radiation exposure.

Continuous arterial spin labeling (CASL) allows quantification of regional CBF by using magnetically labeled water molecules in arterial blood, without the need for exogenous agents (30,31). Thus, the purpose of our study was to measure regional CBF in children with SCD by using CASL perfusion MR imaging and to identify the existence of altered CBF in territories unaffected on conventional MR images.


   Materials and Methods
TOP
 ABSTRACT
 INTRODUCTION
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Subjects
Children with sickle cell disease were recruited into the study from the Pediatric Hematology Clinic at Johns Hopkins Medical Institutes (Baltimore, Md) if they met the following inclusion criteria: (a) homozygous for hemoglobin S; (b) age between 6 and 12 years, inclusive; (c) no history of acute neurologic events, including stroke, transient ischemic attacks, or seizures; (d) no history of receiving chronic blood transfusions or drugs that may affect the central nervous system; (e) parental agreement to sign an informed consent form approved by our institutional review board. Control subjects were the children of faculty and staff at our research center (Johns Hopkins Hospital, Baltimore, Md) and were recruited on the basis of their age (to match as closely as possible that of the patient group) and on the last three inclusion criteria used for the patient group.

Once the patients were recruited into the study, they underwent a thorough standardized neurologic examination performed by a dedicated pediatric neurologist (R.I.). The examination included head circumference measurement and detailed evaluation of cranial nerves; tendon reflexes; and motor, sensory, cerebellar, and gait functions. Identification of any abnormality at the standardized neurologic examination was used to further exclude subjects from the study. The neurologic examination reports from the last visit to the pediatrician were used to screen control subjects prior to final entry into the study.

MR Imaging
MR imaging was performed with a 1.5 T system (ACS-NT; Philips Medical Systems, Best, the Netherlands) equipped with high-performance gradients with a maximum gradient capability of 23 mT/m and a maximum slew rate of 103 mT/m/msec. A dedicated quadrature head coil operating in send-receive mode was used.

The brain MR protocol for imaging in all study participants (patients and control subjects) consisted of sagittal T1-weighted spin-echo imaging (repetition time msec/echo time msec, 587/20) used for localization, transverse T2-weighted fast spin-echo imaging (4,686/100 [effective]), and fast fluid-attenuated inversion-recovery imaging (repetition time msec/effective echo time msec/inversion time msec, 11,000/140/2,725). For T2-weighted fast spin-echo and fast fluid-attenuated inversion-recovery imaging, the in-plane resolution was 0.94 x 0.94 mm and the section thickness was 5.0 mm (1-mm gap). In addition, diffusion-weighted MR imaging was performed in the transverse plane by using a single-shot spin-echo echo-planar readout (3,098/115). Diffusion sensitizing gradients (b = 1,000 sec/mm2) were applied in three orthogonal directions (x, y, and z axes). A reference image with low diffusion weighting (b <= 33 sec/mm2) was also recorded. The in-plane resolution for diffusion-weighted imaging was 2.25 x 0.90 mm, and the section thickness was 5.0 mm (1-mm gap).

The circle of Willis was imaged with single-slab three-dimensional time-of-flight MR angiography (37/3.2, 25° flip angle) with an in-plane resolution of 0.47 x 0.47 mm and a partition thickness of 0.8 mm.

Brain perfusion MR imaging in all subjects (patients and control subjects) was performed by using the CASL method originally described by Alsop and Detre (30,31). Briefly, perfusion sensitization was achieved by using a single send-receive head coil. A 2.4-second radio-frequency pulse was applied at the level of the cervicomedullary junction to achieve flow-driven adiabatic electromagnetic labeling of arterial spins in the carotid and vertebral arteries. The amplitude of the radio-frequency pulse was 3.5 µT, and the gradient strength was 2.5 mT/m. To control for magnetization-transfer effects, a reference image was acquired with sinusoidal modulation of the radio-frequency envelope with a frequency of 250 Hz, thereby achieving simultaneous inversion of two parallel planes leading to a net of zero on the labeled arterial water spins (31). This method allowed for control of magnetization-transfer artifacts throughout the entire brain, thus enabling us to perform whole-brain perfusion imaging (31). To reduce the sensitivity to arterial transit time of this method, the acquisition was delayed by 1.2 seconds after the labeling prepulse. A flow-compensated single-shot spin-echo echo-planar (5,000/36) readout was used to obtain fifteen 8-mm-thick transverse sections separated by a 1-mm gap, with an in-plane resolution of 3.75 x 3.75 mm. The sections were acquired in ascending order to reduce the remaining intravascular labeled spins by means of the natural "crushing" effect (31). Fifty pairs of labeled and control volumes were acquired consecutively to enhance the signal-to-noise ratio, for a total acquisition time of 8 minutes 20 seconds.

All patients underwent conventional MR imaging, including diffusion-weighted imaging and MR angiography, without sedation. Based on their ability to comfortably identify all intracranial structures without limitations, two of three experienced neuroradiologists (K.K.O., F.B.P., E.R.M.) agreed in consensus that all MR images were of diagnostic quality. MR angiograms in two children with SCD and fast fluid-attenuated inversion-recovery MR images in a third child with SCD were slightly degraded by nonphysiologic motion-related artifacts.

Hematocrit Levels
Venous blood was drawn from the patients with SCD at the time of MR imaging in order to determine hematocrit levels. Hematocrit levels were measured by using an automated analyzer (Sysmex SE-9500; Roche, Indianapolis, Ind). Our institutional review board did not allow us to draw venous blood from control subjects.

Image Processing and Analysis
Isotropic (trace-weighted) diffusion-weighted images were generated online by calculating the geometric mean of the three orthogonal diffusion-sensitized images (32).

Perfusion MR images were sent to an off-line workstation (Enterprise; Sun Microsystems, Palo Alto, Calif) for further postprocessing. To produce high-quality whole-brain perfusion MR images in unsedated children, the following postprocessing procedure was developed and implemented by using IDL (Research Systems, Boulder, Colo). Because voxel size is anisotropic in perfusion acquisitions, a rigid-body motion-correction algorithm, commonly used in functional MR imaging (33), could not be applied successfully. Therefore, another algorithm was developed. First, pair-wise subtraction of labeled and control images was performed. Then, the absolute difference between each control and labeled image was calculated individually for the 50 averages. The mean and SD over the 50 individually subtracted volumes were calculated, and pairs that showed an averaged subtracted signal larger than 2 SD were discarded from the final averaging under the assumption that this large signal in the subtracted image was mainly due to motion artifacts. In a further step, each individual pair of subtracted images was screened visually to further remove dubious pairs of labeled and control images. The major advantage of this method is its robustness for discarding any signal that might not be due primarily to perfusion; the drawback of this method is that the signal-to-noise ratio varies among subjects owing to a variable number of averages in the final image.

In order to calculate absolute CBF, we used the expression previously derived by Alsop and Detre (30):

in which M0 is the value of equilibrium magnetization, {Delta}M is the difference between labeled and control magnetizations, T1 is the tissue T1 (1.15 seconds), T1RF is the T1 in the presence of off-resonance irradiation (0.75 second), T1a is blood T1 (1.2 seconds), {alpha} is labeling efficiency and is equal to 1, {lambda} is the tissue-to-blood partition coefficient (0.98), {delta} is tissue transit time (2 seconds), f is CBF in milliliters per second per gram, and w is the predelay time between labeling and acquisition. To facilitate comparison with previously published material, all numeric values used for the calculation of f come from Alsop and Detre (30).

Measurement of CBF in the major cerebral arterial territories—anterior cerebral artery (ACA), middle cerebral artery (MCA), and posterior cerebral artery (PCA)—was based on the anatomic definition of Tatu et al (34). For each study participant, CBF was measured by using regions of interest manually drawn independently by either of two experienced neuroradiologists (K.K.O, E.R.M.) to outline the gray matter of the left and right ACA and MCA territories on eight consecutive sections and the gray matter of the left and right PCA territories on four consecutive sections.

Conventional MR images and source images, as well as targeted maximum intensity projections of the MR angiograms, were reviewed by two neuroradiologists (K.K.O., E.R.M.) with special attention to the presence of (a) hyperintensities in white matter and basal ganglia on T2-weighted fast spin-echo and fast fluid-attenuated inversion-recovery images; (b) acute infarction on isotropic diffusion-weighted images; (c) focal or diffuse changes in the caliber of intracranial portions of the internal carotid arteries, basilar artery, and major branches up to second-division branches on MR angiograms; and (d) completeness of and asymmetries in the circle of Willis. Signal intensity characteristics on T2-weighted fast spin-echo and fast fluid-attenuated inversion-recovery images, as well as anatomic location, were used to differentiate pathologic hyperintensities from Virchow-Robin spaces. Disagreements between the reviewers were resolved by means of discussion and consensus.

Statistical Analysis
Comparison of the average CBF between the SCD group and the control group was performed for each arterial territory by using an unpaired t test and within each group by using a paired t test. To detect significant differences between corresponding arterial territories in the left and right hemispheres, an asymmetry ratio R was defined as follows:

where fL and fR are CBF in the left and right territories, respectively. Then, one can associate the ratio R with a central-reduced normal variable K(R), defined as follows:

where µR and {sigma}R are nonbiased estimators of the mean and SD, respectively, of R over a normal population, calculated with data from the group of volunteers.

Average age was compared for the two groups by using an unpaired t test. Finally, by using the Pearson product-moment correlation, total CBF (sum of average CBF from all six territories) was correlated with hematocrit level and age in the SCD group and with age alone in the control group. For all statistical tests used, P values less than .05 were considered to indicate significant differences.


   Results
TOP
 ABSTRACT
 INTRODUCTION
 Materials and Methods
Results
Discussion
 REFERENCES
 
Eighteen patients with SCD (six girls, 12 boys; average age at time of imaging, 8.7 years; range, 6–12 years) and seven control subjects (six girls, one boy; average age at time of imaging, 11.0 years; range, 8–15 years) fulfilled the inclusion criteria and were entered into the study between July 2000 and January 2002. None of the SCD patients had a neurologic abnormality at the standardized examination, and all control subjects passed the screen on the basis of the neurologic examination report from their last visit to a pediatrician. Three of the 18 patients with SCD entered into the study had a history of recurrent unprovoked headaches.

The age difference between the SCD and control groups was not significant (P = .08). Hematocrit levels were available for 15 SCD patients and ranged from 0.189 to 0.230, with an average value of 0.209. Three children refused to undergo a blood draw at the time of imaging.

Sixteen of the 18 patients and all control subjects underwent CASL perfusion MR imaging. Two patients did not undergo CASL perfusion MR imaging because they were scheduled for the MR study immediately after a software upgrade to the MR unit, which temporarily disabled our CASL capability. CBF maps were successfully generated in 14 of the 16 patients (Fig 1) and in all control subjects by using CASL perfusion MR images. In the remaining two patients, the CASL perfusion MR images were severely corrupted by motion artifacts and could not be salvaged with our motion-detection algorithm.



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  		Figure 1. Transverse whole-brain CBF maps in an 11-year-old neurologically asymptomatic girl with SCD. CBF maps generated with CASL perfusion MR images (5,000/36) demonstrate good differentiation between gray and white matter, with elevated CBF in gray matter (129 mL/min/100 g) and no apparent asymmetry in CBF between left and right hemispheres.

 
Conventional MR Imaging Evaluation
Conventional MR imaging did not demonstrate any abnormal hyperintensities on T2-weighted images or acute infarctions in 17 patients and all control subjects. In one patient, there were two small (<5-mm) hyperintense lesions in the white matter of both frontal lobes (Fig 2) on T2-weighted images; these lesions were isointense to white matter on isotropic diffusion-weighted images. MR angiography did not demonstrate abnormal narrowing or dilatation of the cerebral vasculature, and the circle of Willis was complete without appreciable asymmetries in any of the 18 patients and in all control subjects. There was complete agreement between the two reviewers.



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  		Figure 2. SCD in a 7-year-old neurologically asymptomatic boy (patient 1 in the Table). A, B, Consecutive transverse fast fluid-attenuated inversion-recovery MR images (11,000/140/2,725) at the level of the lateral ventricles and corona radiata demonstrate two small high-signal-intensity lesions (arrows) in white matter of both frontal lobes. C-E, Coronal targeted maximum intensity projections from three-dimensional time-of-flight MR angiogram (37/3.2, 25° flip angle) of the circle of Willis demonstrate no abnormalities.

 
CBF Comparison between SCD and Control Groups
In the ACA territory, the average CBF was 151.7 mL/min/100 g ± 46.1 (SD) in the SCD group (n = 14) and 91.4 mL/min/100 g ± 10.4 in the control group (n = 7). In the MCA territory, these values were 151.8 mL/min/100 g ± 42.5 in the SCD group and 94.3 mL/min/100 g ± 9.4 in the control group. In the PCA territory these values were 159.6 mL/min/100 g ± 40.7 in the SCD group and 119.8 mL/min/100 g ± 16.4 in the control group. Mean CBF in the SCD group was significantly higher in all three territories (P < .001 for ACA and MCA, P < .003 for PCA). When the average CBF of all territories was compared, the difference between the two groups persisted: Average CBF was 152.8 mL/min/100 g ± 42.5 in the SCD group and 97.6 mL/min/100 g ± 10.2 in the control group (P < .001) (Fig 3).



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  		Figure 3. Bar graph demonstrates significant increase in total and territorial CBF in children with SCD (black bars) as compared with CBF in control subjects (gray bars). ACA = anterior cerebral artery, MCA = middle cerebral artery, PCA = posterior cerebral artery.

 
CBF Comparison among Territories
Compared with CBF on the left side, there was a marked decrease in CBF in the right ACA and MCA territories in three patients with SCD and a profound decrease in all three territories on the right in a fourth patient (Fig 4) (Table). None of the these four patients had abnormalities visible on MR angiograms, and only one patient (patient 1) had two small (<5-mm) hyperintense lesions on T2-weighted images in the deep white matter between the ACA and MCA territories of both frontal lobes (Fig 2). No differences were observed between right and left territories in the control group.



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  		Figure 4. Transverse whole-brain CBF maps in a 9-year-old neurologically asymptomatic girl with SCD (patient 4 in the Table). CBF maps generated with CASL perfusion MR images (5,000/36) demonstrate definite decrease in CBF in gray matter of the right cerebral hemispheres in comparison with that on the left for all three vascular territories.

 

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  		Average CBF in Four Patients with SCD with Significant Differences between Cerebral Hemispheres

 
In the control group, the average CBF in the PCA territory was greater than that in the ACA (P < .001) and MCA (P = .001) territories, and the average CBF in the ACA territory was lower than that in MCA territory (P = .04). In the SCD group, there was no difference in the average CBF among the different territories.

Total CBF versus Hematocrit Level and Age
Average total CBF did not correlate with hematocrit level (r = 0.05) and age (r = 0.001) in the SCD group. Average total CBF also did not correlate with age in the control group (r = -0.1).


   Discussion
TOP
 ABSTRACT
 INTRODUCTION
 Materials and Methods
Results
 Discussion
REFERENCES
 
Factors that may influence brain tissue perfusion in children with SCD are abnormal hemoglobin; PaO2 and PaCO2; large vessel disease involving the terminal portion of the internal carotid artery, basilar artery, and major branches; and small vessel disease resulting from altered physical properties of red blood cells within small cerebral arterioles (17,27,35). The last factor is probably important mechanistically in up to 20% of children with SCD and may partly explain the presence of subclinical and clinical brain infarcts in the absence of large vessel disease (27). Perfusion MR imaging may provide information about the effects of small vessel disease, hemoglobin, PaO2, and PaCO2 on brain tissue perfusion that is usually unattainable with conventional MR imaging, MR angiography, or transcranial Doppler sonography.

In this study, we were able to demonstrate the feasibility of CASL perfusion MR imaging to quantify CBF in unsedated children with SCD and in control subjects. Our results show that patients with SCD have a significant increase in gray matter CBF in all cerebral arterial territories as compared with results in control subjects. The observed elevated baseline CBF in our patients with SCD concurs with results of previous studies (23,36) in which PET and xenon-enhanced CT were used. This elevated CBF was due, in part, to low hematocrit levels. Specifically, a reduction in blood viscosity or oxygen delivery to the brain with resultant vasodilation is thought to be responsible for an increase in CBF (37). Cerebral oxygen consumption may also influence the effect of hematocrit level on whole-brain CBF in children with SCD (38). The consequence of this chronic adaptive cerebral vasodilation is secondary depletion of the brain’s reserve capacity in the face of occasional decreases in cerebral perfusion pressure, which renders children with SCD susceptible to distal-field metabolic dysfunction, ischemia, and eventual infarction.

More important, we were able to identify four neurologically asymptomatic children with SCD who had a significant reduction in CBF (compared with an elevated baseline CBF) in nine arterial territories on the right side, without associated demonstrable large arterial disease on MR angiograms. Furthermore, only one out of those four patients had two small subclinical infarcts on conventional MR images, and only one of the two subclinical infarcts (in the right frontal lobe) was actually located between arterial territories with decreased CBF. The underlying cause of the territorial decrease in CBF may be related to arteriolar occlusion due to sludging by sickled red blood cells (39) and resultant local disturbances in PaO2 and PaCO2.

Our ability to show territorial reductions in CBF in four patients underscores the potential of CASL perfusion MR imaging for further study of the effects of small vessel disease on brain tissue perfusion in SCD. On the other hand, the ability of CASL perfusion MR imaging—or, for that matter, any perfusion imaging technique—to allow prospective identification of patients with SCD who are at risk for clinical and subclinical brain infarcts and cognitive decline remains to be assessed. Currently, therapeutic decisions in most SCD clinical trials are based on transcranial Doppler sonographic results, which have been shown to enable prospective prediction of clinical infarction (6–8). Whether perfusion MR imaging will help refine therapeutic decisions based on transcranial Doppler sonographic findings and outperform transcranial Doppler sonography for prediction of subclinical infarcts and cognitive decline requires further evaluation (7).

The lack of correlation between total CBF and age in the SCD and control groups is probably due to the peculiarity of the age ranges in both groups (SCD group: 6–12 years; control subjects: 8–15 years). In the pediatric age group, CBF is lowest during the neonatal period; increases rapidly during early childhood, peaking at age 7 years; and then gradually decreases toward adult values in early adolescence (40,41). The lack of correlation between total CBF and hematocrit level in the SCD group was probably related to the tight range of hematocrit levels (0.189–0.230) and the relatively small number of patients in our study. Authors of previous studies reporting a strong correlation between CBF and hematocrit level actually evaluated the effect on CBF of a wide range of hematocrit levels in children before and after blood transfusions (36).

Interestingly, a significant difference in CBF between the PCA territory and both the ACA and the MCA territories was observed in the control group. Our results are in agreement with recently published PET data (41) that demonstrate regional differences in CBF of young children. These differences in regional CBF may be related to the differences previously described (40) for total cerebral blood flow as assessed with computed sonography. Another possible explanation may be related to the shorter path from the labeling plane to tissue perfused by the PCA compared with the path to tissue perfused by the MCA and ACA, and the relatively higher CBF in the PCA territory may be related to overestimated transport time from the labeling plane.

Children with SCD have been studied with a variety of perfusion imaging techniques, including oxygen 15–enhanced PET, xenon-enhanced CT, and gadolinium-enhanced MR imaging (5,23,26,27,29). Disadvantages of PET perfusion imaging are related to availability of radiotracers and equipment and the use of unnecessary radiation. The latter limitation makes PET unattractive for evaluating children who require multiple follow-up studies. Furthermore, compared with MR imaging techniques, PET does not allow simultaneous imaging of subclinical infarcts and large vessel disease. Similar limitations apply to xenon-enhanced CT. Gadolinium-enhanced perfusion MR imaging, on the other hand, while practical and relatively noninvasive, does not provide quantitative measures of CBF without complicated deconvolution techniques, which are prone to miscalibration and artifacts (27). Specifically, in children with SCD, in whom any large intracranial artery may be affected and any arterial territory may be compromised, the ability to prospectively choose appropriate arterial input functions and internal control territories may be severely limited. An example of these limitations was demonstrated in a report recently published by Kirkham et al (27) on gadolinium-enhanced perfusion MR imaging. In that article, the authors did not report actual measures of CBF but qualitatively compared different vascular territories. Additionally, despite no reported adverse effects from intravenous administration of gadolinium chelates in children with SCD (26,27), institutional review boards are often reluctant to approve protocols that involve any kind of intravenous contrast agent in this patient group.

CASL is a perfusion MR imaging technique that does not require intravenous administration of exogenous contrast agents and relies instead on an endogenous diffusible tracer (electromagnetically labeled arterial blood protons) for quantification of CBF (30,31). However, there are also some issues regarding the absolute quantification of CBF with CASL imaging. First, in this study we did not measure the longitudinal relaxation time (T1) but used previously published values for both blood and tissue T1. While this assumption was acceptable for the control group, the T1 values for brain tissue and blood can be abnormally short in patients with SCD (42). Second, regions of prolonged mean transit time or delayed transit time will produce maps with decreased CBF. While these defects in CBF can be clearly depicted, absolute CBF values should be regarded with caution because one cannot with a single time point differentiate between reduced CBF and prolonged mean transit time. Third, the labeling efficiency ({alpha} value) in patients with SCD can be very different from that in healthy control subjects, due to the increased arterial blood velocity, leading to different adiabatic inversion efficiency in patients with SCD.

Another important point to emphasize is that the average CBF in the gray matter of our control group (91.4 mL/min/100 g tissue) was high compared with data published in the PET literature (43,44). However, compared with average CBF measurements obtained with CASL MR techniques, our results fall within the upper normal range of previously published results (45,46). The difference between PET and CASL MR imaging is probably related to limitations inherent to each technique and to corresponding approximations made in the mathematical models used to calculate CBF.

This study was limited by the lack of monitoring of factors that may influence CBF, such as cardiac and respiratory rates, blood pressure, O2 saturation, PaO2, and PaCO2 during CASL MR perfusion imaging and by the relatively small sample size. Also, our inability to better match age and sex between the SCD and control groups may have compromised some of our results.

In conclusion, CASL perfusion MR imaging is a noninvasive method that demonstrated higher baseline quantitative CBF in the cortex of children with SCD when compared with that in control subjects. There was a significant decrease in baseline CBF in territories depicted as unaffected on conventional MR images and MR angiograms in four children with SCD. Further work is needed to assess the ability of CASL perfusion MR imaging to facilitate prospective identification of children with SCD at risk for developing subclinical infarction and cognitive decline.


   FOOTNOTES
 
Abbreviations: ACA = anterior cerebral artery, CASL = continuous arterial spin labeling, CBF = cerebral blood flow, MCA = middle cerebral artery, PCA = posterior cerebral artery, SCD = sickle cell disease

Author contributions: Guarantor of integrity of entire study, E.R.M.; study concepts and design, E.R.M.; literature research, K.K.O., E.R.M.; clinical studies, R.I., C.A.F., J.F.C.; data acquisition, K.K.O., X.G., N.W.; data analysis/interpretation, F.B.P., K.K.O., X.G.; statistical analysis, X.G.; manuscript preparation, K.K.O., X.G., E.R.M.; manuscript definition of intellectual content, P.C.M.v.Z., E.R.M.; manuscript editing, P.C.M.v.Z., E.R.M., R.I., J.F.C.; manuscript revision/review, P.C.M.v.Z., E.R.M.; manuscript final version approval, E.R.M.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 Materials and Methods
Results
 Discussion
 REFERENCES
 

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