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The effect of preterm birth on neonatal cerebral vasculature studied with magnetic resonance angiography at 3 Tesla
www.elsevier.com/locate/ynimg NeuroImage 32 (2006) 1050 – 1059
The effect of preterm birth on neonatal cerebral vasculature studied with magnetic resonance angiography at 3 Tesla Christina Malamateniou,a,⁎ Serena J. Counsell,a Joanna M. Allsop,a Julie A. Fitzpatrick,a Latha Srinivasan,b Frances M. Cowan,a,b Jo V. Hajnal,a and Mary A. Rutherforda a
Robert Steiner MRI Unit, Imaging Sciences Department, Hammersmith Hospital Campus, Imperial College London, London, UK Department of Paediatrics, Queen Charlotte's and Chelsea Hospital, Imperial College London, London, UK
b
Received 3 February 2006; accepted 23 May 2006 Available online 24 July 2006 Preterm birth is associated with a high incidence of neurodevelopmental deficits. Magnetic resonance imaging (MRI) has proved to be a valuable tool for monitoring development in the preterm brain. We used a dedicated time-of-flight (TOF) magnetic resonance angiography (MRA) protocol at 3 Tesla (3T) optimized to assess morphological characteristics of the neonatal cerebral vessels associated with preterm birth in a sample of 37 infants. We found statistically significant decreased tortuosity in all proximal segments of the cerebral vasculature (anterior, middle and posterior cerebral arteries) in the preterm infants imaged at term equivalent age compared to the term born infants, with no differences in vessel diameter between the two groups. This distinct phenotype of decreased tortuosity was shown to persist until 18 months of age in longitudinal MRA studies in infants born preterm, suggesting that this is not a delay in maturation. Biparietal head diameter measurements were significantly smaller in the preterm at term infants and were inversely correlated with middle cerebral artery tortuosity measurements in both the term born and the preterm at term infants. To our knowledge, this is the first systematic MRA study on the effect of preterm delivery on neonatal cerebral vasculature. Our intention is to build on the findings of this study by combining the data with other measurements of brain growth and vascular haemodynamics to understand more about the interdependence of vessel and brain development and their relationship to prematurity. © 2006 Elsevier Inc. All rights reserved. Keywords: Neonates; Magnetic resonance angiography; Prematurity; Vessel morphology; 3 tesla
Introduction Preterm birth is associated with a high incidence of poor neurodevelopmental outcome including motor disability and neurocognitive impairment (Marlow et al., 2005). In vivo imaging ⁎ Corresponding author. Fax: +44 208 3833038. E-mail address: [email protected] (C. Malamateniou). Available online on ScienceDirect (www.sciencedirect.com). 1053-8119/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2006.05.051
techniques can help improve our understanding of the anatomical correlates for these deficits. Magnetic resonance imaging (MRI) is a non-invasive in vivo method that is ideally suited to identify and characterize changes in immature neural tissue. Recent neuroimaging MRI studies have identified subtle differences in brain development in infants born preterm and imaged at term equivalent age when they were compared with term born infants. These findings include delays in cortical folding (Ajayi-Obe et al., 2000), decreased cortical (Inder et al., 1999) and deep grey matter volumes (Boardman et al., 2003; Inder et al., 2005) and diffuse white matter abnormalities (Huppi et al., 1998; Maalouf et al., 1999; Counsell et al., 2003). The etiology behind these deviations in growth and development is not well understood. Ultrasound studies have explored the functional characteristics of the cerebral vasculature in preterm infants, which is closely anatomically and physiologically linked with neural tissue development (Seydel, 2001). Those studies report an increase of arterial cerebral velocities (d'Orey et al., 1999) and resistance index (Pezzati et al., 2002) along with a decrease of pulsatility index (Robel-Tillig et al., 1999) with advancing gestational age. Additionally, an increase in cerebral blood flow (CBF) volume along with a decrease in resistance and pulsatility indices with increasing postmenstrual age (Kehrer et al., 2003, 2004) has been reported. Ultrasound imaging lacks the spatial resolution that would allow a more detailed and thorough investigation of the structural characteristics of neonatal vasculature. The narrow imaging window due to the ossification of the fontanelles limits examinations much beyond term age and also makes some vessels, such as the posterior cerebral arteries, practically difficult to insonate. To our knowledge, there are as yet no systematic in vivo MRI studies on the development of cerebral vessels in the preterm infant. Based on the findings of recent neuroimaging MRI studies and physiological information provided by ultrasound examinations, we hypothesized that preterm delivery alters the development of cerebral vasculature. The aim of this study was to compare morphological characteristics of the neonatal cerebral vessels of preterm infants imaged at term equivalent age and term born
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infants. We used magnetic resonance angiography (MRA) images acquired at 3 Tesla (3T). MRA is a non-invasive, in vivo method that can be implemented to image the neonatal cerebral vasculature without administration of contrast. It requires no additional preparation and can follow after the standard neonatal MRI protocols of T1- and T2-weighted and diffusion imaging. Furthermore, MRI at 3T has the advantage of increased signal-to-noise ratio (SNR) within a given scanning time (Al-Kwifi et al., 2000; Willinek et al., 2003) and therefore improves visibility of neonatal vessels, which are both smaller and have relatively slow flow (d'Orey et al., 1999). By combining 3T imaging with parallel imaging, we can achieve approximately the same SNR or resolution in a shorter scanning time (Pruessmann, 2005) and decrease the likelihood of artifacts (Larkman et al., 2005) due to infant motion. MR angiography at 3T is therefore an excellent imaging capability for studying the effect of preterm birth on the morphology of the neonatal cerebral vasculature.
Materials and methods Patient selection In this prospective observational study, we scanned a total of 75 preterm at term and term born infants whose postmenstrual age (PMA) at scan ranged between 36 and 44 weeks. The preterm infants were part of a large preterm cohort study and the term infants were scanned for different clinical conditions. All conventional T1and T2-weighted images were assessed by an experienced radiologist for the presence of overt white matter (WM) or basal ganglia (BG) focal lesions. From this initial sample size, we excluded infants for (i) technical reasons (motion artifacts, n = 3) and for (ii) clinical reasons (either vascular-related diseases, n = 10, such as Sturge–Weber syndrome [SWS], neonatal stroke, retinopathy of prematurity [ROP] or abnormal conventional T1- and T2weighted MRI scan, n = 25) (Fig. 1) resulting in a sample size of 37 infants whose scans were considered either normal or without focal pathology and whose underlying diagnosis was not a disorder with a known vascular component.
Fig. 1. Exclusion criteria of technical and clinical nature applied on our initial sample size of 75 infants resulted in a final sample size of 37 infants.
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The final sample size consisted of 22 preterm infants and 15 term born infants. The preterm infants had a median gestational age (GA) of 29.6 weeks (range 25.7–33) scanned at term equivalent age, median 40.53 weeks (range 36.3–43.4). The term born infants had a median GA of 39.3 weeks (range 37–41 weeks) and their median PMA at scan was 41.1 weeks (range 37.6–41.6), which was not significantly greater than that for the preterm infants (P = 0.31). The median birth weight (BW) of the preterm infants was 1.27kg (range 0.65–1.85) with their median weight at scan being 2.90kg (range 1.70–3.67kg). The median BW of the term infants was 3.24kg (range 1.87–4.41) with their median weight at scan being 3.16kg (range 1.70–4.10kg), not significantly different from that of the preterm infants scanned at term equivalent (P = 0.13). Patient preparation Ethical approval for this study was granted by the hospital Research Ethics Committee (2003/6564 and 2003/6517). Informed parental consent was obtained prior to each scan. Infants were imaged either in natural sleep or, where necessary, after sedation with oral chloral hydrate (20–30mg/kg) to prevent image degradation from motion artifacts. They were positioned supine and their head was immobilized using a pillow, which was evacuated with suction to fit snugly around the infant's head. Gradient acoustic noise is increased at 3T. Therefore, ear protection was used for each infant. This comprised of silicon-based dental putty (President putty, Coltene/Whaledent, 750 Corporate Drive, Mahwah, New Jersey, USA) and mini-muffs (Natus MiniMuffs, Natus Medical Inc, San Carlos, CA, USA) to keep it in place, achieving an attenuation of approximately 30dB. Temperature was maintained and monitoring of the infants' vital signs such as heart rate and oxygen saturation was performed throughout the scan. A pediatrician was present throughout the MRI examination (Rutherford, 2002). MRI data acquisition We used a 3T Philips Intera MR scanner (Best, The Netherlands). Both three-dimensional (3D) time-of-flight (TOF) and phase contrast (PC) angiographic methods (Bosmans et al., 2001) were tested for this study. PC MRA, a flow-dependent angiographic method that does not require contrast enhancement, has been described as diagnostically useful when imaging the slow flowing blood after careful adjustment of the velocity encoding factor (VENC) (Ozsarlak et al., 2004), and it is also known to be superior for background brain tissue suppression compared to the TOF method. Nevertheless, in our study PC MRA was associated with the presence of some image degrading artifacts such as (i) pulsatility ghosting artifact from the internal carotid artery (ICA) in the phase encoding direction overlaid on the proximal middle cerebral arteries (MCA) segments and (ii) venous signal “contamination” from the transverse sinuses in the posterior fossa obscuring the visualization of the peripheral branches of the posterior cerebral arteries (PCA). Also it took approximately 2 minutes longer than the TOF MRA method for the same resolution and anatomic coverage; therefore, its use in this study was discontinued. We applied two different 3D TOF MRA protocols; initial examinations were performed with a standard commercially available protocol and subsequently a higher resolution protocol, the result of an optimization study for imaging the neonatal cerebral vasculature (Malamateniou et al., 2005), was used. Protocol parameters appear in Table 1. For the optimized protocol specifically, we used TR = 19ms, FA = 16°, TE = 8.05ms, FOV = 175mm with an RFOV = 80%,
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Table 1 Detailed imaging parameters for the standard preset commercially available protocol for studying the cerebral vasculature of adults and the optimized neonatal 3D TOF MRA acquisition MRA imaging parameters
TR (ms), FOV/RFOV, VOXEL TE (ms), matrix size, scan %, size FA (degrees) coverage (cm) (mm3)
Adult preset protocol
23 3.5 20
Neonatal optimized protocol
19 8.1 16
160/100 193 × 304 64% 7 cm 175/80 288 × 288 100% 6 cm
ECHO Parallel imaging
0.53× Partial CLEAR, no 0.83× SENSE 1.40 mm3 Anisotropic 0.61× Full SENSE 2.00 in the 0.61× phase encoding 0.61 mm3 direction Isotropic
resolution 0.6 × 0.6 × 0.6mm3 isotropic, with a scanning time of 5:30min. We used a SENSE (Pruessmann et al., 1999; van den Brink et al., 2003) factor of 2.00 in the phase encoding direction to further decrease the scanning time and five multiple overlapping chunks to cover the whole volume in order to minimize slow flow saturation at the peripheral arterial branches. A saturation slab was applied at the superior sagittal sinus to suppress venous blood flow. The TOF MRA acquisitions were planned using a two-dimensional (2D) PC MRA survey scan acquired in the sagittal plane and anatomic survey images in transverse and coronal planes. The selected imaging slab was orientated perpendicular to the ICA and provided coverage of the vascular tree from just below the cavernous segment of the ICA to approximately 1cm above the pericallosal branches of the anterior cerebral artery (ACA). Maximum intensity projections (MIPs) were generated for each infant in three different planes: axial, coronal and sagittal. Rotational images from multiple projections were created to improve visualization of overlapping vessels. These MR angiograms were obtained following a routine neonatal imaging protocol, which included structural T1- and T2-weighted images and diffusion weighted acquisitions. Each infant was scanned at least once at term age. Longitudinal studies were performed in 3 term and 7 preterm infants from birth until 18months of age allowing the identification of potential morphological changes over time. Qualitative visual analysis of the vasculature The acquired images, the source images and the MIPs in all three planes, were visually assessed on the MR scanner console.
Number of slices and slice thickness (mm)
Chunks Scan time (number and order) (minutes) coil
100 slices, overcontiguous, 0.7 mm
1 chunk
5′11
T/R head
100 slices, contiguous, 5 chunks 0.3 mm descending SENSE head
5′30
They were checked for patient head motion or for other MRAassociated artifacts such as “venetian blind” artifacts (Blatter et al., 1993) in order to exclude scans with poor vessel visibility or vessel blurring. The remaining images were blindly reviewed focussing on any differences on the size, shape, morphology or number of the vessels that would suggest an underlying alteration in vascular development (Harrigan et al., 2002; Rosenstein et al., 1998). Quantitative analysis of the vasculature Diameter Diameter, a measure of radial vessel size, was quantified using ImageJ medical image analysis software (http://www.rsb.info.nih. gov/ij, version 1.32) on the high resolution MRA images (n = 14, including 5 term and 9 preterm at term infants) for accurate vessel lumen depiction. The full-width-at-half-maximum (FWHM) criterion was applied, as suggested by Hoogeveen et al. (1998) for vessel diameter measurement. A signal intensity curve was generated, with signal intensity plotted against distance (Fig. 2A) along a line drawn perpendicular to the course of the vessel. The profile was fitted with a spline and its width determined at half maximum amplitude, relative to the baseline signal (Fig. 3), which was estimated from a region of interest drawn in a relatively avascular location close to the vessel. The diameters of the proximal branches of the MCA (M1 segment) and PCA (P1 segment) for both the left and the right side were measured in the transverse plane of the MIP image. Excessive overlap of the left and right branches of the ACAs in all MIP
Fig. 2. Vessel diameter (A), tortuosity (B) and head circumference and head diameter measurements (C) using image analysis software and the transverse MIP images. In the third image (C), which is the product of the application of the edge detection filter on the MIP, the rim of the subcutaneous fat around the cranial cavity is visualized.
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Fig. 3. Signal intensity plot for vessel diameter measurements using the full-width-at-half-maximum (FWHM) criterion. The peak in this plot corresponds to the signal intensity from the vessel and the flat part represents the background brain tissue.
planes made diameter quantification unreliable in 11 out of 14 cases. The results were plotted against GA, PMA and birth weight. The effect of infant's gender and artery's laterality (right or left) on those measurements was also examined. Tortuosity In order to quantify the differences in morphology in the vasculature between the preterm and the term infants in an objective way, we used the concept of tortuosity as a measure of vascular shape complexity. Vascular tortuosity is described as a measure of the “frequency and amplitude of the oscillations along a vessel” (Eze et al., 2000). It has been quantified in the past to study vessels in infants with retinopathy of prematurity (ROP) (Hart et al., 1999; Heneghan et al., 2002) and in adults with atherosclerosis (Smedby et al., 1993; Del Corso et al., 1998) and in tumour vessels (Bullitt et al., 2005) using different methods. The diversity of clinical needs has been an impediment to the establishment of a standardized, widely available method for tortuosity quantification. We quantified tortuosity using the distance factor (DF) defined (Bullitt et al., 2003) by DF ¼
Standardized vessel length between defined end points : Length of the straight line with same end points
Analysis was performed by manually tracing along vessels using the segmented line function of the medical image analysis software ImageJ. A standardized anatomical length of three centimeters starting from the origin of the vessels at the ICA (for the ACA and MCA) or at the basilar artery (for the PCA) was used. This included most of the proximal cerebral vasculature to approximately the first branch point in all subjects. The traced contour line followed the midline of the vessel and in cases where there were branches within this predefined length, the bigger in caliber, more proximal and more clearly identified branch was followed. Quantification of cerebral artery tortuosity was performed in the plane, where the vessels concerned were best visualized with minimum overlap. This “optimal plane” was the transverse for the MCAs and the PCAs (Fig. 2B) and the sagittal for the ACAs. The degree of tortuosity was confirmed qualitatively in the remaining imaging planes but quantification was not feasible due to excessive vessel overlap. For the quantification of the ACA, only the vessel that was most clearly visualized on the sagittal MIP images was measured. For the MCAs and PCAs, the transverse plane proved
sufficient for the manual quantification of both the right and the left arterial segments. Three independent examiners measured tortuosity once in a preterm at term and once in a term infant in the left and right MCA. The coefficient of variation for the inter-observer variability was 2%. Similarly intra-observer variability was determined by a single observer measuring three times the left and right MCA of a preterm at term and a term infant and was less than 1.5%. Data were checked for normality using the Shapiro–Wilk test and statistical analysis was performed using either the unpaired t test or the Mann–Whitney test as appropriate. Distance factor measurements were plotted against GA, PMA at scan and birth weight. The effect of infant's gender and laterality of the artery (right or left) on the measurements was also examined. Seven preterm and three term infants had at least one followup scan. The median PMA at the initial scan for the preterm infants was 40.7weeks with a range of 36.9–42.6weeks. The median PMA at the follow-up scan for the preterm infants was 17.3 months with a range of 39.7 weeks–17.5months. The median PMA of the term infants for the initial scan was 40.4 weeks with a range of 37.6–41.1weeks. The median PMA of the term infants for the follow-up scan was 48.6weeks with a range of 48.3– 50.1 weeks. We attempted to use exactly the same imaging slab position in the follow-up scans and to replicate the DF measurement anatomical landmarks having as reference the scan closer to term age for the term and the preterm infants. We used the paired t test to compare the measurements of the initial and follow-up scans. Head circumference (HC) and head diameter From visual inspection, we have previously observed that the shape of the head may sometimes dictate the shape of the vasculature. In order to examine the effect of head size and shape on vessel diameter and morphology we measured HC and head diameter using ImageJ. We performed HC measurements on the transverse MIP angiographic images and used the edge detection filter to enhance the margins of the cranial cavity, as defined by the subcutaneous fat high signal intensity rim. The nose and ears were manually excluded from this measurement. We then used the segmented line function to surround the cranial cavity and measure its circumference (Fig. 2C). The data obtained correlated very well with the direct physical measurement of head circumferences performed
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also plotted against diameter, tortuosity, GA, PMA at scan and birth weight. Results Qualitative visual analysis of the vasculature
Fig. 4. Head circumference measured with image analysis software (y axis) showed excellent correlation (P = 0.0001) with the physical measurement (x axis).
close to the time of the scan at term age (n = 24, P < 0.0001, r2 = 0.90) as shown in Fig. 4. Head diameters were measured on the same plane and image type front-to-back (fronto-occipital diameter) and left-to-right (biparietal diameter). Each measurement was repeated 3 times and the mean of these values was used as the final result. Interobserver variability of three independent examiners quantifying head circumference and head diameter in a preterm at term and a term infant once was less than 0.5%. Intra-observer variability of the same observer measuring head circumference and diameter three times in a preterm at term and a term infant was less than 0.5%. All results were compared for the preterm at term and term born group and for males and females and were
Visual analysis of the MR angiograms revealed that in the preterm infants at term equivalent age, the proximal segments of all cerebral arteries were less tortuous than the corresponding arteries in the term born infants. This was most obvious when assessing the MCAs in the transverse plane (Fig. 5) but it was also observed in the remaining arteries and in all imaging planes (Fig. 6). The pattern and shape of the vasculature in the term born infants was very similar to that of the adult (Figs. 7A and B) in agreement with the literature (Osborn, 1980). However, the vessels of the preterm infants appeared to be thinner and were usually sparser in the periphery with fewer visible branches and bifurcations when compared to the term born infants' vasculature, which appeared far more complex. In the longitudinal MRA studies of preterm and term born subjects, the size and number of visible vessels and vascular branches mainly in the peripheral cerebral vasculature increased with advancing PMA at scan but the shape of the proximal segments of the cerebral arteries remained unchanged at all time points studied up to 18 months of age (Fig. 8). Quantitative analysis of the vasculature Diameter Although on qualitative analysis the preterm at term infants' vessel diameters appeared smaller than those of the term born infants, on quantitative analysis there was no statistically significant
Fig. 5. Transverse MIP MRA images of preterm infants imaged at term (top row: A–E) and term born infants (bottom row: F–J). Note the visual differences in vessel morphology, focusing on the decreased tortuosity of the preterm infants' proximal cerebral vasculature compared to that of the term born infants.
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Fig. 6. The MRA MIP images for a preterm at term (A–C) and a term born infant (D–F) in all three planes: sagittal (A and D), coronal (B and E) and transverse (C and F). The differences in arterial tortuosity between preterm and term infants are overt in all three orthogonal imaging planes but can be quantified only in those planes where the vessels have minimum overlap (optimal planes). Those planes are the transverse for the MCAs and PCAs and the sagittal for the ACAs.
difference in measured vessel diameters; in fact, preterm infants at term had slightly larger diameters for both the MCAs and the PCAs (Table 2). There was no statistical difference between left and right MCAs and PCAs for both the preterm at term (P = 0.95 and P = 0.54) and the term born infants (P = 0.92 and P = 0.53), respectively. Gender did not influence these measurements. Also no linear correlations were observed between GA, PMA and birth weight with diameter, although diameters showed an increase with PMA that did not reach significance. Tortuosity Using the DF measure of tortuosity, there was a statistically significant difference in all three major vessels between the two groups of infants, with less tortuosity in the preterm infants (Fig. 9). There were no significant differences between tortuosity values for the right and left arteries in either term or preterm infants and a mean value was therefore used. In the preterm, infants tortuosity was not associated with GA at birth, gender, birth weight or PMA at scan. Similarly in the term infants, there was no correlation between tortuosity and birth weight, gender, GA at birth, chronological age at scan or postmenstrual age at time of scan.
The absence of an association between tortuosity and PMA at scan was further quantitatively confirmed in the longitudinal MRA studies (P = 0.13). Tortuosity measurements between the initial and follow-up scans in both the preterm and term infants were not statistically different (P = 0.21). The persistent phenotype that was observed in the proximal vascular segments in the preterm infants indicates that the lack of tortuosity does not appear to be a delay in maturation. Head circumference and head diameter There was no difference in the fronto-occipital head diameter at scan (Fig. 10) and in HC at scan (Fig. 11) between the preterm at term and the term born infants. There was a statistically significant difference in the biparietal diameter between these two groups (Table 3). Boys and girls had similar head biometry measurements. In term born infants, mean MCA tortuosity showed a negative linear correlation with biparietal head diameter at scan, but there was no similar relationship for the mean ACA or the mean PCA tortuosity. A negative correlation between the mean MCA tortuosity and biparietal diameter was also found for the preterm infants. Also in the term infants, HC and biparietal head diameter at scan increased linearly with GA, PMA and BW whereas in the preterm infants HC, biparietal and fronto-occipital head diameter at scan increased linearly only with PMA.
Discussion
Fig. 7. Adult (A) and term born infant (B) 3D TOF MRA images showing that the adult-type tortuosity in the proximal cerebral vessels is already established at term age.
In this study, we have used 3D TOF MRA on a 3T MRI scanner to identify and characterize a vascular phenotype associated with preterm birth. Analysis of MR angiograms of preterm infants imaged at term equivalent age and term born infants revealed systematic and statistically significant differences. The cerebral vessels of the preterm group appeared sparser, particularly in the distal branches, as compared to the term born infants. Although the reduced visibility of the distal vessels might suggest that the vessel diameters were smaller, in fact measurements of the major vessels showed no significant differences between the preterm at term and the term born infants. Nevertheless, we acknowledge that this might be due to the smaller number of infants with high resolution MRA included in the diameter measurement study.
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Fig. 8. A preterm infant (born at 30 weeks gestational age) scanned longitudinally four times (from left to right) at 35(A), 38 (B), 44 (C) weeks PMA and at 18 months of age (D). Note the persistent phenotype of decreased proximal vessel tortuosity in all scans and the increase of peripheral vessel visibility with advancing age.
Quantitative analysis confirmed the visual impression of decreased tortuosity in the proximal cerebral vessels in the preterm infants imaged at term. Furthermore, the subjects we were able to follow-up revealed that this preterm phenotype is persistent, with the shape of the proximal vessels remaining less tortuous even when there is substantial growth of distal branches. To date and to our knowledge, this is the first systematic MR angiography study on the effect of preterm delivery on neonatal cerebral vasculature. Previous research (Kulenovic and Dilberovic, 2004) has studied cerebral blood vessels in 20 fetuses with GA between 16 and 36 weeks and in 5 full-term stillborn cadavers. This postmortem study reported that in early fetal life the arteries are thin and have a straight pattern. Progressive changes were observed for all brain arteries, which begun to assume a more curved pattern with increasing GA of the specimens. However, by their nature cadaver studies cannot compare preterm and term born infants at the same PMA, as we did. In addition, studying vascular geometry using postmortem methods is quite challenging as the neonatal brain, being friable, collapses once removed from the skull and the normal CSF spaces are lost. Therefore, the vessels, closely linked to brain anatomy, also lose their spatial relationships. MR angiography provides a non-invasive in vivo method by which cerebral vessels can be examined in respect to the neighboring brain anatomy and without disturbing their geometric features.
A limitation of our study is the application of a 2D metric for the quantification of the 3D vascular tree. Qualitative analysis in three orthogonal viewing planes confirmed that the finding of decreased tortuosity is a three-dimensional phenomenon. However, the fact that this decrease in tortuosity is clearly seen in all projections gives confidence that a 2D metric can characterize this difference between the two groups. By choosing the plane where the vessels appeared clearly and well separated, and using standardized projection orientations in all subjects, we achieved clearly significant results. The distance factor therefore provided an adequate surrogate measure that reflects changes in tortuosity in 3D. Tortuosity of the proximal cerebral vessels is only one component of cerebral vascular tree complexity with no reference to other aspects of vessel morphology such as shape, size and number of ramifications or the architectural characteristics of more distal branches. All these facets are automatically included in a visual inspection by the human eye. This may explain why vascular structures that can be instantly and systematically recognized as different as shown in Fig. 5, yield distance factor measurements with ranges that overlap even though they are statistically significantly different. Nevertheless, DF does provide a simple, straightforward and convenient tortuosity quantification method with high intra- and inter-observer reproducibility. We chose to use a standardized length of measurement of the first three centimeters from the origin of the artery instead of an
Table 2 Summary of the mean values of cerebral arteries diameter and tortuosity measurements in the term born and the preterm infants imaged at term equivalent age Mean values
Vessel morphology measurements ACA tortuosity
MCA tortuosity
PCA tortuosity
MCA PCA diameter diameter (mm) (mm)
Preterm 1.172 1.292 1.281 1.011 0.893 at term Term born 1.320 1.419 1.447 0.994 0.867 Statistical P = 0.0001 P = 0.0003 P = 0.0002 P = 0.34 P = 0.14 significance Note the statistically significant decreased tortuosity in all cerebral arteries of the preterm at term infants. There was no statistically significant difference in vessel diameter.
Fig. 9. Cerebral arteries tortuosity in proximal segments of ACA, MCA and PCA arteries in the preterm at term and the term born infants using the metric of DF.
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Table 3 Summary of the mean values of head biometry measurements in the term born and the preterm infants imaged at term equivalent age Mean values
Preterm at term Term born Statistical significance
Head biometry measurements Head circumference (cm)
Biparietal head diameter (L/R) (cm)
Fronto-occipital head diameter (F/B) (cm)
35.380
8.840
12.415
36.281 P = 0.07
9.687 P = 0.0001
12.297 P = 0.32
Note the statistically significant decreased biparietal head diameters in the preterm at term infants.
Fig. 10. Head diameter (HD) measured in preterm at term and term born infants. Fronto-occipital (F-O) and biparietal (B-P) HD were compared revealing statistically significant differences in the latter. The clinical significance of this finding remains unknown.
anatomic landmark such as the bifurcation of the arterial tree, which can vary among different subjects. This predefined length was adequate to translate the visual finding into distance factor measurements for the neonatal vessels. Possible reasons for our finding of decreased tortuosity in association with preterm delivery may be found by reviewing the factors that are known to affect vascular development and putting them into the context of prematurity. Vessel development is influenced by oxygen levels (Risau, 1997; Plate, 1999; Breier, 2000; Kurz, 2000; Carmeliet, 2003; Ferrara et al., 2003) and by fatty acid concentrations. Preterm infants are delivered into an environment that is relatively hyperoxic compared to the oxygen levels in the uterus, where a relative hypoxia stimulates vessel growth and development. In addition, the preterm infant is deficient in numerous factors normally passed over the placenta during the third trimester of pregnancy, for example, essential fatty acids such as arachidonic acid (AA) and docosahexaenoic acid (DHA), which are structural and functional constituents of cell membranes and have a fundamental role in both neural and
vascular development and function (Crawford et al., 1997). The alteration in vessel development may therefore reflect the altered metabolic and gaseous environment. The relationship of this finding to other abnormalities in brain development needs to be further investigated. It is possible that aberrant vascular development may underlie the disorders in other body systems found in children and adults who were born preterm (Barker, 1988; Singhal et al., 2004; Gluckman and Hanson, 2004; Gluckman et al., 2005). Another factor contributing to the shaping of cerebrovascular morphology may be the anatomy of the surrounding brain tissue. This study has shown a negative linear correlation between MCA tortuosity and biparietal head diameter measurements in both the term and the preterm infants at term equivalent age. Nevertheless, no similar correlations between head biometry and vessel tortuosity in other cerebral arteries were observed. Computer-based image registration of the vessels and the brain tissue in these subjects is currently underway in an attempt to identify the possible influence of brain anatomy on vascular development. The clinical significance and the relationship of this distinct vascular phenotype with brain haemodynamics remains unknown, and we hope that further studies of physiologic parameters such as blood flow velocities and brain perfusion will provide additional information. Initial results of MRI arterial spin labeling (ASL) perfusion measurements in 9 preterm infants imaged at term and 11 term born infants have shown significantly increased brain perfusion values for the preterm infants (Miranda et al., 2004). However, MRI perfusion measurements in neonates are still in an experimental stage and require further development to facilitate interpretation of results and make them suitable for larger studies. Our intention is to build on the findings of this study by combining the data with other measurements of brain growth and vascular haemodynamics to understand more about the interdependence of vessel and brain development and their relationship to prematurity.
Acknowledgments
Fig. 11. Head circumference (HC) measurements at scan in the two groups. The preterm at term infants had slightly – but not statistically significant – smaller HC.
We would like to gratefully acknowledge the Greek State Scholarships Foundation, the Medical Research Council, the Health Foundation, the Academy of Medical Sciences and the Philips Medical Systems for research grant support. We would also like to thank parents and children that took part in this study.
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References Ajayi-Obe, M., Saeed, N., Cowan, F.M., Rutherford, M.A., Edwards, A.D., 2000. Reduced development of cerebral cortex in extremely preterm infants. Lancet 356 (9236), 1162–1163. Al-Kwifi, O., Emery, D.J., Wilman, A.H., 2000. Vessel contrast at three Tesla in time-of-flight magnetic resonance angiography of the intracranial and carotid arteries. Magn. Reson. Imaging 20 (2), 181–187. Barker, D.J., 1988. Childhood causes of adult diseases. Arch. Dis. Child. 63 (7), 867–869. Blatter, D.D., Bahr, A.L., Parker, D.L., Robison, R.O., Kimball, J.A., Perry, D.M., Horn, S., 1993. Cervical carotid MR angiography with multiple overlapping thin-slab acquisition: comparison with conventional angiography. Am. J. Roentgenol. 161 (6), 1269–1277. Boardman, J.P., Bhatia, K., Counsell, S.J., Allsop, J.M., Kapellou, O., Rutherford, M.A., Edwards, A.D., Hajnal, J.V., Rueckert, D., 2003. An evaluation of deformation-based morphometry applied to the developing human brain and detection of volumetric changes associated with preterm birth. MICCAI. Lect. Notes Comput. Sci. 2878, 697–704. Bosmans, H., Wilms, G., Dymarkowski, S., Marchal, G., 2001. Basic principles of MR angiography. Eur. J. Radiol. 38 (1), 2–9. Breier, G., 2000. Angiogenesis in embryonic development—A review. Placenta 21 (Suppl. A), S11–S15. Bullitt, E., Gerig, G., Pizer, S.M., Lin, W., Aylward, S.R., 2003. Measuring tortuosity of the intracerebral vasculature from MRA images. IEEE Trans. Med. Imaging 22 (9), 1163–1171. Bullitt, E., Zeng, D., Gerig, G., Aylward, S., Joshi, S., Smith, J.K., Lin, W., Ewend, M.G., 2005. Vessel tortuosity and brain tumor malignancy: a blinded study. Acad. Radiol. 12 (10), 1232–1240. Carmeliet, P., 2003. Angiogenesis in health and disease. Nat. Med. 9 (6), 653–660. Counsell, S.J., Allsop, J.M., Harrison, M.C., Larkman, D.J., Kennea, N.L., Kapellou, O., Cowan, F.M., Hajnal, J.V., Edwards, A.D., Rutherford, M.A., 2003. Diffusion-weighted imaging of the brain in preterm infants with focal and diffuse white matter abnormality. Pediatrics 112 (1 Pt. 1), 1–7. Crawford, M.A., Costeloe, K., Ghebremeskel, K., Phylactos, A., Skirvin, L., Stacey, F., 1997. Are deficits of arachidonic and docosahexaenoic acids responsible for the neural and vascular complications of preterm babies? Am. J. Clin. Nutr. 66 (4 Suppl.), 1032S–1041S. Del Corso, L., Moruzzo, D., Conte, B., Agelli, M., Romanelli, AM., Pastine, F., Protti, M., Pentimone, F., Baggiani, G., 1998. Tortuosity, kinking, and coiling of the carotid artery: expression of atherosclerosis or aging? Angiology 49 (5), 361–371. d'Orey, C., Mateus, M., Guimaraes, H., Ramos, I., Melo, M.J., Silva, J., Ramos, E., Montenegro, N., Barros, H., Santos, N., 1999. Neonatal cerebral Doppler: arterial and venous flow velocity measurements using color and pulsed Doppler system. J. Perinat. Med. 27 (5), 352–361. Eze, C.U., Gupta, R., Newman, D.L., 2000. A comparison of quantitative measures of arterial tortuosity using sine wave simulations and 3D wire models. Phys. Med. Biol. 45 (9), 2593–2599. Ferrara, N., Gerber, H.P., LeCouter, J., 2003. The biology of VEGF and its receptors. Nat. Med. 9 (6), 669–676. Gluckman, P.D., Hanson, M.A., 2004. Living with the past: evolution, development, and patterns of disease. Science 17 (305 (5691)), 1733–1736. Gluckman, P.D., Cutfield, W., Hofman, P., Hanson, M.A., 2005. The fetal, neonatal, and infant environments-the long-term consequences for disease risk. Early Hum. Dev. 81 (1), 51–59. Harrigan, M.R., Ennis, S.R., Masada, T., Keep, R.F., 2002. Intraventricular infusion of vascular endothelial growth factor promotes cerebral angiogenesis with minimal brain edema. Neurosurgery 50 (3), 589–598. Hart, W.E., Goldbaum, M., Cote, B., Kube, P., Nelson, M.R., 1999. Measurement and classification of retinal vascular tortuosity. Int. J. Med. Inform. 53 (2–3), 239–252. Heneghan, C., Flynn, J., O'Keefe, M., Cahill, M., 2002. Characterization of changes in blood vessel width and tortuosity in retinopathy of prematurity using image analysis. Med. Image Anal. 6 (4), 407–429.
Hoogeveen, R.M., Bakker, C.J., Viergever, M.A., 1998. Limits to the accuracy of vessel diameter measurement in MR angiography. J. Magn. Reson. Imaging 8 (6), 1228–1235. Huppi, P.S., Warfield, S., Kikinis, R., Barnes, P.D., Zientara, G.P., Jolesz, F.A., Tsuji, M.K., Volpe, J.J., 1998. Quantitative magnetic resonance imaging of brain development in premature and mature newborns. Ann. Neurol. 43 (2), 224–235. Inder, T.E., Huppi, P.S., Warfield, S., Kikinis, R., Zientara, G.P., Barnes, P.D., Jolesz, F., Volpe, J.J., 1999. Periventricular white matter injury in the premature infant is followed by reduced cerebral cortical gray matter volume at term. Ann. Neurol. 46 (5), 604–755. Inder, T.E., Warfield, S.K., Wang, H., Huppi, P.S., Volpe, J.J., 2005. Abnormal cerebral structure is present at term in premature infants. Pediatrics 115 (2), 286–294. Kehrer, M., Krageloh-Mann, I., Goelz, R., Schoning, M., 2003. The development of cerebral perfusion in healthy preterm and term neonates. Neuropediatrics 34 (6), 281–286. Kehrer, M., Goelz, R., Schoning, M., 2004. The development of haemodynamics in the extracranial cerebral arteries of healthy preterm and term neonates. Ultrasound Med. Biol. 30 (3), 283–287. Kulenovic, A., Dilberovic, F., 2004. Changes in blood vessels in fetuses 4 to 9 months intrauterine life old by postmortem angiography method. Bosn. J. Basic Med. Sci. 4 (3), 50–54. Kurz, H., 2000. Physiology of angiogenesis. J. Neuro-Oncol. 50 (1–2), 17–35. Larkman, D.J., Atkinson, D., Hajnal, J.V., 2005. Artifact reduction using parallel imaging methods. Top. Magn. Reson. Imaging 15 (4), 267–275. Maalouf, E.F., Duggan, P.J., Rutherford, M.A., Counsell, S.J., Fletcher, A.M., Battin, M., Cowan, F., Edwards, A.D., 1999. Magnetic resonance imaging of the brain in a cohort of extremely preterm infants. J. Pediatr. 135 (3), 351–357. Malamateniou, C., Counsell, S.J., Allsop, J.M., Fitzpatrick, J.A., Cowan, F.M., Rutherford, M.A., Hajnal, J.V., 2005. Optimized magnetic resonance angiography at 3 Tesla for neonates. Proc. Int. Soc. Magn. Reson. Med., Miami, USA, p. 452 (Abstract number 2327). Marlow, N., Wolke, D., Bracewell, M.A., Samara, M., EPICure Study Group, 2005. Neurologic and developmental disability at six years of age after extremely preterm birth. N. Engl. J. Med. 352 (1), 9–19. Miranda, M.J., Olofsson, K., Sidaros, K., 2004. Non-invasive perfusion measurements in term neonates and premature infants using arterial spin labelling. Eur. Soc. Magn. Reson. Neuropediatrics Proc. Osborn, A.G., 1980. Introduction to Cerebral Angiography. Harper and Row, Philadelphia, pp. 239–293. Ozsarlak, O., Van Goethem, J.W., Maes, M., Parizel, P.M., 2004. MR angiography of the intracranial vessels: technical aspects and clinical applications. Neuroradiology 46 (12), 955–972. Pezzati, M., Dani, C., Biadaioli, R., Filippi, L., Biagiotti, R., Giani, T., Rubaltelli, F.F., 2002. Early postnatal Doppler assessment of cerebral blood flow velocity in healthy preterm and term infants. Dev. Med. Child Neurol. 44 (11), 745–752. Plate, K.H., 1999. Mechanisms of angiogenesis in the brain. J. Neuropathol. Exp. Neurol. 58 (4), 313–320. Pruessmann, K.P., 2005. Parallel imaging at high field strength: synergies and joint potential. Top. Magn. Reson. Imaging 15 (4), 237–244. Pruessmann, K.P., Weiger, M., Scheidegger, M.B., Boesiger, P., 1999. SENSE: sensitivity encoding for fast MRI. Magn. Reson. Med. 42 (5), 952–962. Risau, W., 1997. Mechanisms of angiogenesis. Nature 17 (386 (6626)), 671–674. Robel-Tillig, E., Mockel, A., Vogtmann, C., 1999. Normal Doppler ultrasound values of the anterior cerebral artery of premature and newborn infants with reference to cardiac function parameters and intestinal blood flow profile. Z. Geburtshilfe Neonatol. 203 (6), 234–240. Rosenstein, J.M., Mani, N., Silverman, W.F., Krum, J.M., 1998. Patterns of brain angiogenesis after vascular endothelial growth factor administration in vitro and in vivo. Proc. Natl. Acad. Sci. U. S. A. 9 (95 (12)), 7086–7091.
C. Malamateniou et al. / NeuroImage 32 (2006) 1050–1059 Rutherford, M.A., 2002. MRI of the Neonatal Brain. WB Saunders, London, pp. 17–21. Seydel, C., 2001. Developmental biology. Organs await blood vessels' go signal. Science 28 (293 (5539)), 2365. Singhal, A., Cole, T.J., Fewtrell, M., Deanfield, J., Lucas, A., 2004. Is slower early growth beneficial for long-term cardiovascular health? Circulation 9 (109 (9)), 1108–1113. Smedby, O., Hogman, N., Nilsson, S., Erikson, U., Olsson, A.G., Walldius, G., 1993. Two-dimensional tortuosity of the superficial femoral artery in early atherosclerosis. J. Vasc. Res. 30 (4), 181–191.
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van den Brink, J.S., Watanabe, Y., Kuhl, C.K., Chung, T., Muthupillai, R., Van Cauteren, M., Yamada, K., Dymarkowski, S., Bogaert, J., Maki, J.H., Matos, C., Casselman, J.W., Hoogeveen, R.M., 2003. Implications of SENSE MR in routine clinical practice. Eur. J. Radiol. 46 (1), 3–27. Willinek, W.A., Born, M., Simon, B., Tschampa, H.J., Krautmacher, C., Gieseke, J., Urbach, H., Textor, H.J., Schild, H.H., 2003. Time-of-flight MR angiography: comparison of 3.0-T imaging and 1.5-T imaging—Initial experience. Radiology 229 (3), 913–920.
The effect of preterm birth on neonatal cerebral vasculature studied with magnetic resonance angiography at 3 Tesla Christina Malamateniou,a,⁎ Serena J. Counsell,a Joanna M. Allsop,a Julie A. Fitzpatrick,a Latha Srinivasan,b Frances M. Cowan,a,b Jo V. Hajnal,a and Mary A. Rutherforda a
Robert Steiner MRI Unit, Imaging Sciences Department, Hammersmith Hospital Campus, Imperial College London, London, UK Department of Paediatrics, Queen Charlotte's and Chelsea Hospital, Imperial College London, London, UK
b
Received 3 February 2006; accepted 23 May 2006 Available online 24 July 2006 Preterm birth is associated with a high incidence of neurodevelopmental deficits. Magnetic resonance imaging (MRI) has proved to be a valuable tool for monitoring development in the preterm brain. We used a dedicated time-of-flight (TOF) magnetic resonance angiography (MRA) protocol at 3 Tesla (3T) optimized to assess morphological characteristics of the neonatal cerebral vessels associated with preterm birth in a sample of 37 infants. We found statistically significant decreased tortuosity in all proximal segments of the cerebral vasculature (anterior, middle and posterior cerebral arteries) in the preterm infants imaged at term equivalent age compared to the term born infants, with no differences in vessel diameter between the two groups. This distinct phenotype of decreased tortuosity was shown to persist until 18 months of age in longitudinal MRA studies in infants born preterm, suggesting that this is not a delay in maturation. Biparietal head diameter measurements were significantly smaller in the preterm at term infants and were inversely correlated with middle cerebral artery tortuosity measurements in both the term born and the preterm at term infants. To our knowledge, this is the first systematic MRA study on the effect of preterm delivery on neonatal cerebral vasculature. Our intention is to build on the findings of this study by combining the data with other measurements of brain growth and vascular haemodynamics to understand more about the interdependence of vessel and brain development and their relationship to prematurity. © 2006 Elsevier Inc. All rights reserved. Keywords: Neonates; Magnetic resonance angiography; Prematurity; Vessel morphology; 3 tesla
Introduction Preterm birth is associated with a high incidence of poor neurodevelopmental outcome including motor disability and neurocognitive impairment (Marlow et al., 2005). In vivo imaging ⁎ Corresponding author. Fax: +44 208 3833038. E-mail address: [email protected] (C. Malamateniou). Available online on ScienceDirect (www.sciencedirect.com). 1053-8119/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2006.05.051
techniques can help improve our understanding of the anatomical correlates for these deficits. Magnetic resonance imaging (MRI) is a non-invasive in vivo method that is ideally suited to identify and characterize changes in immature neural tissue. Recent neuroimaging MRI studies have identified subtle differences in brain development in infants born preterm and imaged at term equivalent age when they were compared with term born infants. These findings include delays in cortical folding (Ajayi-Obe et al., 2000), decreased cortical (Inder et al., 1999) and deep grey matter volumes (Boardman et al., 2003; Inder et al., 2005) and diffuse white matter abnormalities (Huppi et al., 1998; Maalouf et al., 1999; Counsell et al., 2003). The etiology behind these deviations in growth and development is not well understood. Ultrasound studies have explored the functional characteristics of the cerebral vasculature in preterm infants, which is closely anatomically and physiologically linked with neural tissue development (Seydel, 2001). Those studies report an increase of arterial cerebral velocities (d'Orey et al., 1999) and resistance index (Pezzati et al., 2002) along with a decrease of pulsatility index (Robel-Tillig et al., 1999) with advancing gestational age. Additionally, an increase in cerebral blood flow (CBF) volume along with a decrease in resistance and pulsatility indices with increasing postmenstrual age (Kehrer et al., 2003, 2004) has been reported. Ultrasound imaging lacks the spatial resolution that would allow a more detailed and thorough investigation of the structural characteristics of neonatal vasculature. The narrow imaging window due to the ossification of the fontanelles limits examinations much beyond term age and also makes some vessels, such as the posterior cerebral arteries, practically difficult to insonate. To our knowledge, there are as yet no systematic in vivo MRI studies on the development of cerebral vessels in the preterm infant. Based on the findings of recent neuroimaging MRI studies and physiological information provided by ultrasound examinations, we hypothesized that preterm delivery alters the development of cerebral vasculature. The aim of this study was to compare morphological characteristics of the neonatal cerebral vessels of preterm infants imaged at term equivalent age and term born
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infants. We used magnetic resonance angiography (MRA) images acquired at 3 Tesla (3T). MRA is a non-invasive, in vivo method that can be implemented to image the neonatal cerebral vasculature without administration of contrast. It requires no additional preparation and can follow after the standard neonatal MRI protocols of T1- and T2-weighted and diffusion imaging. Furthermore, MRI at 3T has the advantage of increased signal-to-noise ratio (SNR) within a given scanning time (Al-Kwifi et al., 2000; Willinek et al., 2003) and therefore improves visibility of neonatal vessels, which are both smaller and have relatively slow flow (d'Orey et al., 1999). By combining 3T imaging with parallel imaging, we can achieve approximately the same SNR or resolution in a shorter scanning time (Pruessmann, 2005) and decrease the likelihood of artifacts (Larkman et al., 2005) due to infant motion. MR angiography at 3T is therefore an excellent imaging capability for studying the effect of preterm birth on the morphology of the neonatal cerebral vasculature.
Materials and methods Patient selection In this prospective observational study, we scanned a total of 75 preterm at term and term born infants whose postmenstrual age (PMA) at scan ranged between 36 and 44 weeks. The preterm infants were part of a large preterm cohort study and the term infants were scanned for different clinical conditions. All conventional T1and T2-weighted images were assessed by an experienced radiologist for the presence of overt white matter (WM) or basal ganglia (BG) focal lesions. From this initial sample size, we excluded infants for (i) technical reasons (motion artifacts, n = 3) and for (ii) clinical reasons (either vascular-related diseases, n = 10, such as Sturge–Weber syndrome [SWS], neonatal stroke, retinopathy of prematurity [ROP] or abnormal conventional T1- and T2weighted MRI scan, n = 25) (Fig. 1) resulting in a sample size of 37 infants whose scans were considered either normal or without focal pathology and whose underlying diagnosis was not a disorder with a known vascular component.
Fig. 1. Exclusion criteria of technical and clinical nature applied on our initial sample size of 75 infants resulted in a final sample size of 37 infants.
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The final sample size consisted of 22 preterm infants and 15 term born infants. The preterm infants had a median gestational age (GA) of 29.6 weeks (range 25.7–33) scanned at term equivalent age, median 40.53 weeks (range 36.3–43.4). The term born infants had a median GA of 39.3 weeks (range 37–41 weeks) and their median PMA at scan was 41.1 weeks (range 37.6–41.6), which was not significantly greater than that for the preterm infants (P = 0.31). The median birth weight (BW) of the preterm infants was 1.27kg (range 0.65–1.85) with their median weight at scan being 2.90kg (range 1.70–3.67kg). The median BW of the term infants was 3.24kg (range 1.87–4.41) with their median weight at scan being 3.16kg (range 1.70–4.10kg), not significantly different from that of the preterm infants scanned at term equivalent (P = 0.13). Patient preparation Ethical approval for this study was granted by the hospital Research Ethics Committee (2003/6564 and 2003/6517). Informed parental consent was obtained prior to each scan. Infants were imaged either in natural sleep or, where necessary, after sedation with oral chloral hydrate (20–30mg/kg) to prevent image degradation from motion artifacts. They were positioned supine and their head was immobilized using a pillow, which was evacuated with suction to fit snugly around the infant's head. Gradient acoustic noise is increased at 3T. Therefore, ear protection was used for each infant. This comprised of silicon-based dental putty (President putty, Coltene/Whaledent, 750 Corporate Drive, Mahwah, New Jersey, USA) and mini-muffs (Natus MiniMuffs, Natus Medical Inc, San Carlos, CA, USA) to keep it in place, achieving an attenuation of approximately 30dB. Temperature was maintained and monitoring of the infants' vital signs such as heart rate and oxygen saturation was performed throughout the scan. A pediatrician was present throughout the MRI examination (Rutherford, 2002). MRI data acquisition We used a 3T Philips Intera MR scanner (Best, The Netherlands). Both three-dimensional (3D) time-of-flight (TOF) and phase contrast (PC) angiographic methods (Bosmans et al., 2001) were tested for this study. PC MRA, a flow-dependent angiographic method that does not require contrast enhancement, has been described as diagnostically useful when imaging the slow flowing blood after careful adjustment of the velocity encoding factor (VENC) (Ozsarlak et al., 2004), and it is also known to be superior for background brain tissue suppression compared to the TOF method. Nevertheless, in our study PC MRA was associated with the presence of some image degrading artifacts such as (i) pulsatility ghosting artifact from the internal carotid artery (ICA) in the phase encoding direction overlaid on the proximal middle cerebral arteries (MCA) segments and (ii) venous signal “contamination” from the transverse sinuses in the posterior fossa obscuring the visualization of the peripheral branches of the posterior cerebral arteries (PCA). Also it took approximately 2 minutes longer than the TOF MRA method for the same resolution and anatomic coverage; therefore, its use in this study was discontinued. We applied two different 3D TOF MRA protocols; initial examinations were performed with a standard commercially available protocol and subsequently a higher resolution protocol, the result of an optimization study for imaging the neonatal cerebral vasculature (Malamateniou et al., 2005), was used. Protocol parameters appear in Table 1. For the optimized protocol specifically, we used TR = 19ms, FA = 16°, TE = 8.05ms, FOV = 175mm with an RFOV = 80%,
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Table 1 Detailed imaging parameters for the standard preset commercially available protocol for studying the cerebral vasculature of adults and the optimized neonatal 3D TOF MRA acquisition MRA imaging parameters
TR (ms), FOV/RFOV, VOXEL TE (ms), matrix size, scan %, size FA (degrees) coverage (cm) (mm3)
Adult preset protocol
23 3.5 20
Neonatal optimized protocol
19 8.1 16
160/100 193 × 304 64% 7 cm 175/80 288 × 288 100% 6 cm
ECHO Parallel imaging
0.53× Partial CLEAR, no 0.83× SENSE 1.40 mm3 Anisotropic 0.61× Full SENSE 2.00 in the 0.61× phase encoding 0.61 mm3 direction Isotropic
resolution 0.6 × 0.6 × 0.6mm3 isotropic, with a scanning time of 5:30min. We used a SENSE (Pruessmann et al., 1999; van den Brink et al., 2003) factor of 2.00 in the phase encoding direction to further decrease the scanning time and five multiple overlapping chunks to cover the whole volume in order to minimize slow flow saturation at the peripheral arterial branches. A saturation slab was applied at the superior sagittal sinus to suppress venous blood flow. The TOF MRA acquisitions were planned using a two-dimensional (2D) PC MRA survey scan acquired in the sagittal plane and anatomic survey images in transverse and coronal planes. The selected imaging slab was orientated perpendicular to the ICA and provided coverage of the vascular tree from just below the cavernous segment of the ICA to approximately 1cm above the pericallosal branches of the anterior cerebral artery (ACA). Maximum intensity projections (MIPs) were generated for each infant in three different planes: axial, coronal and sagittal. Rotational images from multiple projections were created to improve visualization of overlapping vessels. These MR angiograms were obtained following a routine neonatal imaging protocol, which included structural T1- and T2-weighted images and diffusion weighted acquisitions. Each infant was scanned at least once at term age. Longitudinal studies were performed in 3 term and 7 preterm infants from birth until 18months of age allowing the identification of potential morphological changes over time. Qualitative visual analysis of the vasculature The acquired images, the source images and the MIPs in all three planes, were visually assessed on the MR scanner console.
Number of slices and slice thickness (mm)
Chunks Scan time (number and order) (minutes) coil
100 slices, overcontiguous, 0.7 mm
1 chunk
5′11
T/R head
100 slices, contiguous, 5 chunks 0.3 mm descending SENSE head
5′30
They were checked for patient head motion or for other MRAassociated artifacts such as “venetian blind” artifacts (Blatter et al., 1993) in order to exclude scans with poor vessel visibility or vessel blurring. The remaining images were blindly reviewed focussing on any differences on the size, shape, morphology or number of the vessels that would suggest an underlying alteration in vascular development (Harrigan et al., 2002; Rosenstein et al., 1998). Quantitative analysis of the vasculature Diameter Diameter, a measure of radial vessel size, was quantified using ImageJ medical image analysis software (http://www.rsb.info.nih. gov/ij, version 1.32) on the high resolution MRA images (n = 14, including 5 term and 9 preterm at term infants) for accurate vessel lumen depiction. The full-width-at-half-maximum (FWHM) criterion was applied, as suggested by Hoogeveen et al. (1998) for vessel diameter measurement. A signal intensity curve was generated, with signal intensity plotted against distance (Fig. 2A) along a line drawn perpendicular to the course of the vessel. The profile was fitted with a spline and its width determined at half maximum amplitude, relative to the baseline signal (Fig. 3), which was estimated from a region of interest drawn in a relatively avascular location close to the vessel. The diameters of the proximal branches of the MCA (M1 segment) and PCA (P1 segment) for both the left and the right side were measured in the transverse plane of the MIP image. Excessive overlap of the left and right branches of the ACAs in all MIP
Fig. 2. Vessel diameter (A), tortuosity (B) and head circumference and head diameter measurements (C) using image analysis software and the transverse MIP images. In the third image (C), which is the product of the application of the edge detection filter on the MIP, the rim of the subcutaneous fat around the cranial cavity is visualized.
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Fig. 3. Signal intensity plot for vessel diameter measurements using the full-width-at-half-maximum (FWHM) criterion. The peak in this plot corresponds to the signal intensity from the vessel and the flat part represents the background brain tissue.
planes made diameter quantification unreliable in 11 out of 14 cases. The results were plotted against GA, PMA and birth weight. The effect of infant's gender and artery's laterality (right or left) on those measurements was also examined. Tortuosity In order to quantify the differences in morphology in the vasculature between the preterm and the term infants in an objective way, we used the concept of tortuosity as a measure of vascular shape complexity. Vascular tortuosity is described as a measure of the “frequency and amplitude of the oscillations along a vessel” (Eze et al., 2000). It has been quantified in the past to study vessels in infants with retinopathy of prematurity (ROP) (Hart et al., 1999; Heneghan et al., 2002) and in adults with atherosclerosis (Smedby et al., 1993; Del Corso et al., 1998) and in tumour vessels (Bullitt et al., 2005) using different methods. The diversity of clinical needs has been an impediment to the establishment of a standardized, widely available method for tortuosity quantification. We quantified tortuosity using the distance factor (DF) defined (Bullitt et al., 2003) by DF ¼
Standardized vessel length between defined end points : Length of the straight line with same end points
Analysis was performed by manually tracing along vessels using the segmented line function of the medical image analysis software ImageJ. A standardized anatomical length of three centimeters starting from the origin of the vessels at the ICA (for the ACA and MCA) or at the basilar artery (for the PCA) was used. This included most of the proximal cerebral vasculature to approximately the first branch point in all subjects. The traced contour line followed the midline of the vessel and in cases where there were branches within this predefined length, the bigger in caliber, more proximal and more clearly identified branch was followed. Quantification of cerebral artery tortuosity was performed in the plane, where the vessels concerned were best visualized with minimum overlap. This “optimal plane” was the transverse for the MCAs and the PCAs (Fig. 2B) and the sagittal for the ACAs. The degree of tortuosity was confirmed qualitatively in the remaining imaging planes but quantification was not feasible due to excessive vessel overlap. For the quantification of the ACA, only the vessel that was most clearly visualized on the sagittal MIP images was measured. For the MCAs and PCAs, the transverse plane proved
sufficient for the manual quantification of both the right and the left arterial segments. Three independent examiners measured tortuosity once in a preterm at term and once in a term infant in the left and right MCA. The coefficient of variation for the inter-observer variability was 2%. Similarly intra-observer variability was determined by a single observer measuring three times the left and right MCA of a preterm at term and a term infant and was less than 1.5%. Data were checked for normality using the Shapiro–Wilk test and statistical analysis was performed using either the unpaired t test or the Mann–Whitney test as appropriate. Distance factor measurements were plotted against GA, PMA at scan and birth weight. The effect of infant's gender and laterality of the artery (right or left) on the measurements was also examined. Seven preterm and three term infants had at least one followup scan. The median PMA at the initial scan for the preterm infants was 40.7weeks with a range of 36.9–42.6weeks. The median PMA at the follow-up scan for the preterm infants was 17.3 months with a range of 39.7 weeks–17.5months. The median PMA of the term infants for the initial scan was 40.4 weeks with a range of 37.6–41.1weeks. The median PMA of the term infants for the follow-up scan was 48.6weeks with a range of 48.3– 50.1 weeks. We attempted to use exactly the same imaging slab position in the follow-up scans and to replicate the DF measurement anatomical landmarks having as reference the scan closer to term age for the term and the preterm infants. We used the paired t test to compare the measurements of the initial and follow-up scans. Head circumference (HC) and head diameter From visual inspection, we have previously observed that the shape of the head may sometimes dictate the shape of the vasculature. In order to examine the effect of head size and shape on vessel diameter and morphology we measured HC and head diameter using ImageJ. We performed HC measurements on the transverse MIP angiographic images and used the edge detection filter to enhance the margins of the cranial cavity, as defined by the subcutaneous fat high signal intensity rim. The nose and ears were manually excluded from this measurement. We then used the segmented line function to surround the cranial cavity and measure its circumference (Fig. 2C). The data obtained correlated very well with the direct physical measurement of head circumferences performed
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also plotted against diameter, tortuosity, GA, PMA at scan and birth weight. Results Qualitative visual analysis of the vasculature
Fig. 4. Head circumference measured with image analysis software (y axis) showed excellent correlation (P = 0.0001) with the physical measurement (x axis).
close to the time of the scan at term age (n = 24, P < 0.0001, r2 = 0.90) as shown in Fig. 4. Head diameters were measured on the same plane and image type front-to-back (fronto-occipital diameter) and left-to-right (biparietal diameter). Each measurement was repeated 3 times and the mean of these values was used as the final result. Interobserver variability of three independent examiners quantifying head circumference and head diameter in a preterm at term and a term infant once was less than 0.5%. Intra-observer variability of the same observer measuring head circumference and diameter three times in a preterm at term and a term infant was less than 0.5%. All results were compared for the preterm at term and term born group and for males and females and were
Visual analysis of the MR angiograms revealed that in the preterm infants at term equivalent age, the proximal segments of all cerebral arteries were less tortuous than the corresponding arteries in the term born infants. This was most obvious when assessing the MCAs in the transverse plane (Fig. 5) but it was also observed in the remaining arteries and in all imaging planes (Fig. 6). The pattern and shape of the vasculature in the term born infants was very similar to that of the adult (Figs. 7A and B) in agreement with the literature (Osborn, 1980). However, the vessels of the preterm infants appeared to be thinner and were usually sparser in the periphery with fewer visible branches and bifurcations when compared to the term born infants' vasculature, which appeared far more complex. In the longitudinal MRA studies of preterm and term born subjects, the size and number of visible vessels and vascular branches mainly in the peripheral cerebral vasculature increased with advancing PMA at scan but the shape of the proximal segments of the cerebral arteries remained unchanged at all time points studied up to 18 months of age (Fig. 8). Quantitative analysis of the vasculature Diameter Although on qualitative analysis the preterm at term infants' vessel diameters appeared smaller than those of the term born infants, on quantitative analysis there was no statistically significant
Fig. 5. Transverse MIP MRA images of preterm infants imaged at term (top row: A–E) and term born infants (bottom row: F–J). Note the visual differences in vessel morphology, focusing on the decreased tortuosity of the preterm infants' proximal cerebral vasculature compared to that of the term born infants.
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Fig. 6. The MRA MIP images for a preterm at term (A–C) and a term born infant (D–F) in all three planes: sagittal (A and D), coronal (B and E) and transverse (C and F). The differences in arterial tortuosity between preterm and term infants are overt in all three orthogonal imaging planes but can be quantified only in those planes where the vessels have minimum overlap (optimal planes). Those planes are the transverse for the MCAs and PCAs and the sagittal for the ACAs.
difference in measured vessel diameters; in fact, preterm infants at term had slightly larger diameters for both the MCAs and the PCAs (Table 2). There was no statistical difference between left and right MCAs and PCAs for both the preterm at term (P = 0.95 and P = 0.54) and the term born infants (P = 0.92 and P = 0.53), respectively. Gender did not influence these measurements. Also no linear correlations were observed between GA, PMA and birth weight with diameter, although diameters showed an increase with PMA that did not reach significance. Tortuosity Using the DF measure of tortuosity, there was a statistically significant difference in all three major vessels between the two groups of infants, with less tortuosity in the preterm infants (Fig. 9). There were no significant differences between tortuosity values for the right and left arteries in either term or preterm infants and a mean value was therefore used. In the preterm, infants tortuosity was not associated with GA at birth, gender, birth weight or PMA at scan. Similarly in the term infants, there was no correlation between tortuosity and birth weight, gender, GA at birth, chronological age at scan or postmenstrual age at time of scan.
The absence of an association between tortuosity and PMA at scan was further quantitatively confirmed in the longitudinal MRA studies (P = 0.13). Tortuosity measurements between the initial and follow-up scans in both the preterm and term infants were not statistically different (P = 0.21). The persistent phenotype that was observed in the proximal vascular segments in the preterm infants indicates that the lack of tortuosity does not appear to be a delay in maturation. Head circumference and head diameter There was no difference in the fronto-occipital head diameter at scan (Fig. 10) and in HC at scan (Fig. 11) between the preterm at term and the term born infants. There was a statistically significant difference in the biparietal diameter between these two groups (Table 3). Boys and girls had similar head biometry measurements. In term born infants, mean MCA tortuosity showed a negative linear correlation with biparietal head diameter at scan, but there was no similar relationship for the mean ACA or the mean PCA tortuosity. A negative correlation between the mean MCA tortuosity and biparietal diameter was also found for the preterm infants. Also in the term infants, HC and biparietal head diameter at scan increased linearly with GA, PMA and BW whereas in the preterm infants HC, biparietal and fronto-occipital head diameter at scan increased linearly only with PMA.
Discussion
Fig. 7. Adult (A) and term born infant (B) 3D TOF MRA images showing that the adult-type tortuosity in the proximal cerebral vessels is already established at term age.
In this study, we have used 3D TOF MRA on a 3T MRI scanner to identify and characterize a vascular phenotype associated with preterm birth. Analysis of MR angiograms of preterm infants imaged at term equivalent age and term born infants revealed systematic and statistically significant differences. The cerebral vessels of the preterm group appeared sparser, particularly in the distal branches, as compared to the term born infants. Although the reduced visibility of the distal vessels might suggest that the vessel diameters were smaller, in fact measurements of the major vessels showed no significant differences between the preterm at term and the term born infants. Nevertheless, we acknowledge that this might be due to the smaller number of infants with high resolution MRA included in the diameter measurement study.
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Fig. 8. A preterm infant (born at 30 weeks gestational age) scanned longitudinally four times (from left to right) at 35(A), 38 (B), 44 (C) weeks PMA and at 18 months of age (D). Note the persistent phenotype of decreased proximal vessel tortuosity in all scans and the increase of peripheral vessel visibility with advancing age.
Quantitative analysis confirmed the visual impression of decreased tortuosity in the proximal cerebral vessels in the preterm infants imaged at term. Furthermore, the subjects we were able to follow-up revealed that this preterm phenotype is persistent, with the shape of the proximal vessels remaining less tortuous even when there is substantial growth of distal branches. To date and to our knowledge, this is the first systematic MR angiography study on the effect of preterm delivery on neonatal cerebral vasculature. Previous research (Kulenovic and Dilberovic, 2004) has studied cerebral blood vessels in 20 fetuses with GA between 16 and 36 weeks and in 5 full-term stillborn cadavers. This postmortem study reported that in early fetal life the arteries are thin and have a straight pattern. Progressive changes were observed for all brain arteries, which begun to assume a more curved pattern with increasing GA of the specimens. However, by their nature cadaver studies cannot compare preterm and term born infants at the same PMA, as we did. In addition, studying vascular geometry using postmortem methods is quite challenging as the neonatal brain, being friable, collapses once removed from the skull and the normal CSF spaces are lost. Therefore, the vessels, closely linked to brain anatomy, also lose their spatial relationships. MR angiography provides a non-invasive in vivo method by which cerebral vessels can be examined in respect to the neighboring brain anatomy and without disturbing their geometric features.
A limitation of our study is the application of a 2D metric for the quantification of the 3D vascular tree. Qualitative analysis in three orthogonal viewing planes confirmed that the finding of decreased tortuosity is a three-dimensional phenomenon. However, the fact that this decrease in tortuosity is clearly seen in all projections gives confidence that a 2D metric can characterize this difference between the two groups. By choosing the plane where the vessels appeared clearly and well separated, and using standardized projection orientations in all subjects, we achieved clearly significant results. The distance factor therefore provided an adequate surrogate measure that reflects changes in tortuosity in 3D. Tortuosity of the proximal cerebral vessels is only one component of cerebral vascular tree complexity with no reference to other aspects of vessel morphology such as shape, size and number of ramifications or the architectural characteristics of more distal branches. All these facets are automatically included in a visual inspection by the human eye. This may explain why vascular structures that can be instantly and systematically recognized as different as shown in Fig. 5, yield distance factor measurements with ranges that overlap even though they are statistically significantly different. Nevertheless, DF does provide a simple, straightforward and convenient tortuosity quantification method with high intra- and inter-observer reproducibility. We chose to use a standardized length of measurement of the first three centimeters from the origin of the artery instead of an
Table 2 Summary of the mean values of cerebral arteries diameter and tortuosity measurements in the term born and the preterm infants imaged at term equivalent age Mean values
Vessel morphology measurements ACA tortuosity
MCA tortuosity
PCA tortuosity
MCA PCA diameter diameter (mm) (mm)
Preterm 1.172 1.292 1.281 1.011 0.893 at term Term born 1.320 1.419 1.447 0.994 0.867 Statistical P = 0.0001 P = 0.0003 P = 0.0002 P = 0.34 P = 0.14 significance Note the statistically significant decreased tortuosity in all cerebral arteries of the preterm at term infants. There was no statistically significant difference in vessel diameter.
Fig. 9. Cerebral arteries tortuosity in proximal segments of ACA, MCA and PCA arteries in the preterm at term and the term born infants using the metric of DF.
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Table 3 Summary of the mean values of head biometry measurements in the term born and the preterm infants imaged at term equivalent age Mean values
Preterm at term Term born Statistical significance
Head biometry measurements Head circumference (cm)
Biparietal head diameter (L/R) (cm)
Fronto-occipital head diameter (F/B) (cm)
35.380
8.840
12.415
36.281 P = 0.07
9.687 P = 0.0001
12.297 P = 0.32
Note the statistically significant decreased biparietal head diameters in the preterm at term infants.
Fig. 10. Head diameter (HD) measured in preterm at term and term born infants. Fronto-occipital (F-O) and biparietal (B-P) HD were compared revealing statistically significant differences in the latter. The clinical significance of this finding remains unknown.
anatomic landmark such as the bifurcation of the arterial tree, which can vary among different subjects. This predefined length was adequate to translate the visual finding into distance factor measurements for the neonatal vessels. Possible reasons for our finding of decreased tortuosity in association with preterm delivery may be found by reviewing the factors that are known to affect vascular development and putting them into the context of prematurity. Vessel development is influenced by oxygen levels (Risau, 1997; Plate, 1999; Breier, 2000; Kurz, 2000; Carmeliet, 2003; Ferrara et al., 2003) and by fatty acid concentrations. Preterm infants are delivered into an environment that is relatively hyperoxic compared to the oxygen levels in the uterus, where a relative hypoxia stimulates vessel growth and development. In addition, the preterm infant is deficient in numerous factors normally passed over the placenta during the third trimester of pregnancy, for example, essential fatty acids such as arachidonic acid (AA) and docosahexaenoic acid (DHA), which are structural and functional constituents of cell membranes and have a fundamental role in both neural and
vascular development and function (Crawford et al., 1997). The alteration in vessel development may therefore reflect the altered metabolic and gaseous environment. The relationship of this finding to other abnormalities in brain development needs to be further investigated. It is possible that aberrant vascular development may underlie the disorders in other body systems found in children and adults who were born preterm (Barker, 1988; Singhal et al., 2004; Gluckman and Hanson, 2004; Gluckman et al., 2005). Another factor contributing to the shaping of cerebrovascular morphology may be the anatomy of the surrounding brain tissue. This study has shown a negative linear correlation between MCA tortuosity and biparietal head diameter measurements in both the term and the preterm infants at term equivalent age. Nevertheless, no similar correlations between head biometry and vessel tortuosity in other cerebral arteries were observed. Computer-based image registration of the vessels and the brain tissue in these subjects is currently underway in an attempt to identify the possible influence of brain anatomy on vascular development. The clinical significance and the relationship of this distinct vascular phenotype with brain haemodynamics remains unknown, and we hope that further studies of physiologic parameters such as blood flow velocities and brain perfusion will provide additional information. Initial results of MRI arterial spin labeling (ASL) perfusion measurements in 9 preterm infants imaged at term and 11 term born infants have shown significantly increased brain perfusion values for the preterm infants (Miranda et al., 2004). However, MRI perfusion measurements in neonates are still in an experimental stage and require further development to facilitate interpretation of results and make them suitable for larger studies. Our intention is to build on the findings of this study by combining the data with other measurements of brain growth and vascular haemodynamics to understand more about the interdependence of vessel and brain development and their relationship to prematurity.
Acknowledgments
Fig. 11. Head circumference (HC) measurements at scan in the two groups. The preterm at term infants had slightly – but not statistically significant – smaller HC.
We would like to gratefully acknowledge the Greek State Scholarships Foundation, the Medical Research Council, the Health Foundation, the Academy of Medical Sciences and the Philips Medical Systems for research grant support. We would also like to thank parents and children that took part in this study.
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References Ajayi-Obe, M., Saeed, N., Cowan, F.M., Rutherford, M.A., Edwards, A.D., 2000. Reduced development of cerebral cortex in extremely preterm infants. Lancet 356 (9236), 1162–1163. Al-Kwifi, O., Emery, D.J., Wilman, A.H., 2000. Vessel contrast at three Tesla in time-of-flight magnetic resonance angiography of the intracranial and carotid arteries. Magn. Reson. Imaging 20 (2), 181–187. Barker, D.J., 1988. Childhood causes of adult diseases. Arch. Dis. Child. 63 (7), 867–869. Blatter, D.D., Bahr, A.L., Parker, D.L., Robison, R.O., Kimball, J.A., Perry, D.M., Horn, S., 1993. Cervical carotid MR angiography with multiple overlapping thin-slab acquisition: comparison with conventional angiography. Am. J. Roentgenol. 161 (6), 1269–1277. Boardman, J.P., Bhatia, K., Counsell, S.J., Allsop, J.M., Kapellou, O., Rutherford, M.A., Edwards, A.D., Hajnal, J.V., Rueckert, D., 2003. An evaluation of deformation-based morphometry applied to the developing human brain and detection of volumetric changes associated with preterm birth. MICCAI. Lect. Notes Comput. Sci. 2878, 697–704. Bosmans, H., Wilms, G., Dymarkowski, S., Marchal, G., 2001. Basic principles of MR angiography. Eur. J. Radiol. 38 (1), 2–9. Breier, G., 2000. Angiogenesis in embryonic development—A review. Placenta 21 (Suppl. A), S11–S15. Bullitt, E., Gerig, G., Pizer, S.M., Lin, W., Aylward, S.R., 2003. Measuring tortuosity of the intracerebral vasculature from MRA images. IEEE Trans. Med. Imaging 22 (9), 1163–1171. Bullitt, E., Zeng, D., Gerig, G., Aylward, S., Joshi, S., Smith, J.K., Lin, W., Ewend, M.G., 2005. Vessel tortuosity and brain tumor malignancy: a blinded study. Acad. Radiol. 12 (10), 1232–1240. Carmeliet, P., 2003. Angiogenesis in health and disease. Nat. Med. 9 (6), 653–660. Counsell, S.J., Allsop, J.M., Harrison, M.C., Larkman, D.J., Kennea, N.L., Kapellou, O., Cowan, F.M., Hajnal, J.V., Edwards, A.D., Rutherford, M.A., 2003. Diffusion-weighted imaging of the brain in preterm infants with focal and diffuse white matter abnormality. Pediatrics 112 (1 Pt. 1), 1–7. Crawford, M.A., Costeloe, K., Ghebremeskel, K., Phylactos, A., Skirvin, L., Stacey, F., 1997. Are deficits of arachidonic and docosahexaenoic acids responsible for the neural and vascular complications of preterm babies? Am. J. Clin. Nutr. 66 (4 Suppl.), 1032S–1041S. Del Corso, L., Moruzzo, D., Conte, B., Agelli, M., Romanelli, AM., Pastine, F., Protti, M., Pentimone, F., Baggiani, G., 1998. Tortuosity, kinking, and coiling of the carotid artery: expression of atherosclerosis or aging? Angiology 49 (5), 361–371. d'Orey, C., Mateus, M., Guimaraes, H., Ramos, I., Melo, M.J., Silva, J., Ramos, E., Montenegro, N., Barros, H., Santos, N., 1999. Neonatal cerebral Doppler: arterial and venous flow velocity measurements using color and pulsed Doppler system. J. Perinat. Med. 27 (5), 352–361. Eze, C.U., Gupta, R., Newman, D.L., 2000. A comparison of quantitative measures of arterial tortuosity using sine wave simulations and 3D wire models. Phys. Med. Biol. 45 (9), 2593–2599. Ferrara, N., Gerber, H.P., LeCouter, J., 2003. The biology of VEGF and its receptors. Nat. Med. 9 (6), 669–676. Gluckman, P.D., Hanson, M.A., 2004. Living with the past: evolution, development, and patterns of disease. Science 17 (305 (5691)), 1733–1736. Gluckman, P.D., Cutfield, W., Hofman, P., Hanson, M.A., 2005. The fetal, neonatal, and infant environments-the long-term consequences for disease risk. Early Hum. Dev. 81 (1), 51–59. Harrigan, M.R., Ennis, S.R., Masada, T., Keep, R.F., 2002. Intraventricular infusion of vascular endothelial growth factor promotes cerebral angiogenesis with minimal brain edema. Neurosurgery 50 (3), 589–598. Hart, W.E., Goldbaum, M., Cote, B., Kube, P., Nelson, M.R., 1999. Measurement and classification of retinal vascular tortuosity. Int. J. Med. Inform. 53 (2–3), 239–252. Heneghan, C., Flynn, J., O'Keefe, M., Cahill, M., 2002. Characterization of changes in blood vessel width and tortuosity in retinopathy of prematurity using image analysis. Med. Image Anal. 6 (4), 407–429.
Hoogeveen, R.M., Bakker, C.J., Viergever, M.A., 1998. Limits to the accuracy of vessel diameter measurement in MR angiography. J. Magn. Reson. Imaging 8 (6), 1228–1235. Huppi, P.S., Warfield, S., Kikinis, R., Barnes, P.D., Zientara, G.P., Jolesz, F.A., Tsuji, M.K., Volpe, J.J., 1998. Quantitative magnetic resonance imaging of brain development in premature and mature newborns. Ann. Neurol. 43 (2), 224–235. Inder, T.E., Huppi, P.S., Warfield, S., Kikinis, R., Zientara, G.P., Barnes, P.D., Jolesz, F., Volpe, J.J., 1999. Periventricular white matter injury in the premature infant is followed by reduced cerebral cortical gray matter volume at term. Ann. Neurol. 46 (5), 604–755. Inder, T.E., Warfield, S.K., Wang, H., Huppi, P.S., Volpe, J.J., 2005. Abnormal cerebral structure is present at term in premature infants. Pediatrics 115 (2), 286–294. Kehrer, M., Krageloh-Mann, I., Goelz, R., Schoning, M., 2003. The development of cerebral perfusion in healthy preterm and term neonates. Neuropediatrics 34 (6), 281–286. Kehrer, M., Goelz, R., Schoning, M., 2004. The development of haemodynamics in the extracranial cerebral arteries of healthy preterm and term neonates. Ultrasound Med. Biol. 30 (3), 283–287. Kulenovic, A., Dilberovic, F., 2004. Changes in blood vessels in fetuses 4 to 9 months intrauterine life old by postmortem angiography method. Bosn. J. Basic Med. Sci. 4 (3), 50–54. Kurz, H., 2000. Physiology of angiogenesis. J. Neuro-Oncol. 50 (1–2), 17–35. Larkman, D.J., Atkinson, D., Hajnal, J.V., 2005. Artifact reduction using parallel imaging methods. Top. Magn. Reson. Imaging 15 (4), 267–275. Maalouf, E.F., Duggan, P.J., Rutherford, M.A., Counsell, S.J., Fletcher, A.M., Battin, M., Cowan, F., Edwards, A.D., 1999. Magnetic resonance imaging of the brain in a cohort of extremely preterm infants. J. Pediatr. 135 (3), 351–357. Malamateniou, C., Counsell, S.J., Allsop, J.M., Fitzpatrick, J.A., Cowan, F.M., Rutherford, M.A., Hajnal, J.V., 2005. Optimized magnetic resonance angiography at 3 Tesla for neonates. Proc. Int. Soc. Magn. Reson. Med., Miami, USA, p. 452 (Abstract number 2327). Marlow, N., Wolke, D., Bracewell, M.A., Samara, M., EPICure Study Group, 2005. Neurologic and developmental disability at six years of age after extremely preterm birth. N. Engl. J. Med. 352 (1), 9–19. Miranda, M.J., Olofsson, K., Sidaros, K., 2004. Non-invasive perfusion measurements in term neonates and premature infants using arterial spin labelling. Eur. Soc. Magn. Reson. Neuropediatrics Proc. Osborn, A.G., 1980. Introduction to Cerebral Angiography. Harper and Row, Philadelphia, pp. 239–293. Ozsarlak, O., Van Goethem, J.W., Maes, M., Parizel, P.M., 2004. MR angiography of the intracranial vessels: technical aspects and clinical applications. Neuroradiology 46 (12), 955–972. Pezzati, M., Dani, C., Biadaioli, R., Filippi, L., Biagiotti, R., Giani, T., Rubaltelli, F.F., 2002. Early postnatal Doppler assessment of cerebral blood flow velocity in healthy preterm and term infants. Dev. Med. Child Neurol. 44 (11), 745–752. Plate, K.H., 1999. Mechanisms of angiogenesis in the brain. J. Neuropathol. Exp. Neurol. 58 (4), 313–320. Pruessmann, K.P., 2005. Parallel imaging at high field strength: synergies and joint potential. Top. Magn. Reson. Imaging 15 (4), 237–244. Pruessmann, K.P., Weiger, M., Scheidegger, M.B., Boesiger, P., 1999. SENSE: sensitivity encoding for fast MRI. Magn. Reson. Med. 42 (5), 952–962. Risau, W., 1997. Mechanisms of angiogenesis. Nature 17 (386 (6626)), 671–674. Robel-Tillig, E., Mockel, A., Vogtmann, C., 1999. Normal Doppler ultrasound values of the anterior cerebral artery of premature and newborn infants with reference to cardiac function parameters and intestinal blood flow profile. Z. Geburtshilfe Neonatol. 203 (6), 234–240. Rosenstein, J.M., Mani, N., Silverman, W.F., Krum, J.M., 1998. Patterns of brain angiogenesis after vascular endothelial growth factor administration in vitro and in vivo. Proc. Natl. Acad. Sci. U. S. A. 9 (95 (12)), 7086–7091.
C. Malamateniou et al. / NeuroImage 32 (2006) 1050–1059 Rutherford, M.A., 2002. MRI of the Neonatal Brain. WB Saunders, London, pp. 17–21. Seydel, C., 2001. Developmental biology. Organs await blood vessels' go signal. Science 28 (293 (5539)), 2365. Singhal, A., Cole, T.J., Fewtrell, M., Deanfield, J., Lucas, A., 2004. Is slower early growth beneficial for long-term cardiovascular health? Circulation 9 (109 (9)), 1108–1113. Smedby, O., Hogman, N., Nilsson, S., Erikson, U., Olsson, A.G., Walldius, G., 1993. Two-dimensional tortuosity of the superficial femoral artery in early atherosclerosis. J. Vasc. Res. 30 (4), 181–191.
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van den Brink, J.S., Watanabe, Y., Kuhl, C.K., Chung, T., Muthupillai, R., Van Cauteren, M., Yamada, K., Dymarkowski, S., Bogaert, J., Maki, J.H., Matos, C., Casselman, J.W., Hoogeveen, R.M., 2003. Implications of SENSE MR in routine clinical practice. Eur. J. Radiol. 46 (1), 3–27. Willinek, W.A., Born, M., Simon, B., Tschampa, H.J., Krautmacher, C., Gieseke, J., Urbach, H., Textor, H.J., Schild, H.H., 2003. Time-of-flight MR angiography: comparison of 3.0-T imaging and 1.5-T imaging—Initial experience. Radiology 229 (3), 913–920.