Comparison of CT and CMR for detection and quantification of carotid artery calcification: the Rotterdam Study

This study was carried out within the framework of the Rotterdam Study, a prospective population-based study among middle-aged and elderly persons [11]. Between 2003 and 2006, all participants that visited the research center were invited to undergo multi-detector computed tomography (MDCT) to quantify vascular calcification in multiple vessels, including the carotid artery bifurcation [12]. In total 2,524 participants were scanned.

From October 2007 onwards, carotid CMR was incorporated in the Rotterdam Study. Between 2007 and 2012, we invited 2,666 participants to undergo CMR of the carotid arteries to study atherosclerotic disease. These participants were selected on the basis of the presence of atherosclerosis in at least one carotid artery on ultrasound examination (defined as intima-media thickness >2.0 mm in one or both carotid arteries), which is regularly performed in all Rotterdam Study participants. In total 1,982 participants underwent carotid CMR. From these 1,982, 808 participants had also undergone a CT-examination. Due to image artifacts or low image quality (n = 31, or errors in the CMR registration process needed for analysis (n = 93) 124 participants were excluded, leaving 684 participants with usable CT and CMR data for the current study. The mean time interval between CT scan and CMR scan was 4.9 years (standard deviation 1.2 years).

We performed a non-enhanced CT-examination (16-or 64-slice MDCT Somatom Sensation, Siemens, Forchheim, Germany) that reached from the aortic arch to the intracranial vasculature, to visualize calcification in the extracranial carotid arteries. The detailed information regarding the scan protocol is described elsewhere [12]. In short, the following scan parameters were used: 16 x 0.75 mm collimation, 120 kVp, 100 effective mAs, and 0.5 s rotation time, with a normalized pitch of 1. Images were reconstructed with an effective slice width of 1 mm, a reconstruction interval of 0.5 mm, and a medium sharp convolution kernel [12]. Calcification in the extra-cranial carotid artery was measured bilaterally within three centimeters proximal and distal of the bifurcation and was automatically quantified with dedicated commercially available software (syngo calcium scoring, Siemens, Germany) [12]. Calcification volumes in both carotid arteries were expressed in cubic millimeters (mm³) [13] (Fig. 1).

CMR of the carotid arteries was performed on a single 1.5-T scanner (GE Healthcare, Milwaukee, WI, USA) with a dedicated bilateral phased-array surface coil (Machnet, Eelde, The Netherlands). The high-resolution images were obtained using a standardized protocol [14]. First, both carotids were identified by means of two-dimensional (2D) time-of-flight MR angiography. Second, high-resolution CMR sequences were planned to image the carotid bifurcations on both sides. These sequences consisted of four 2D sequences in the axial plane, namely a proton density weighted (PDw)-fast spin echo (FSE)-black blood (BB) sequence (in-plane resolution 130/160 x 130/128 = 0.8 x 1 cm); a PDw-FSE-BB with an increased in-plane resolution (in-plane resolution 130/224 x 130/160 = 0.5 x 0.8 cm); a PDw-echo planar image (EPI) sequence (in-plane resolution 130/160 x 70/160 = 0.8 x 0.4 cm); and a T2w-EPI sequence (in-plane resolution 130/160 x 70/160 = 0.8 x 0.4 cm). Additionally, we performed two 3D sequences, namely a 3D-T1w-gradient echo (GRE) sequence (in-plane resolution 180/192 x 180/180 = 0.9 x 1 cm), and a 3D phased-contrast MR angiography (in-plane resolution 180/256 x 180/128 = 0.7 x 1.4 cm) (Additional file 1: Table S3). The total scanning time was approximately 30 min [14]. Calcification was evaluated bilaterally within three centimeters proximal and distal of the bifurcation [12]. All calcification measurements on CMR were performed by one trained physician under the supervision of an experienced neuroradiologist. We performed an intra- and inter-observer reproducibility analysis on a random set of 30 CMR examinations. The intra- and inter-agreement was very good [Cohens’ Kappa : 0.91 (95% CI 0.82–0.99) and 0.94 (95% CI 0.86–0.99)], respectively. We defined calcification as a hypointense region in the plaque on all sequences. We manually annotated and segmented calcification in all plaques using a standardized approach. First, we pre-processed all images using a method that has been described extensively before [15]. This starts with a bias correction to reduce the intensity inhomogeneity characteristic in CMR [15]. Subsequently, the carotid artery in all images was rigidly registered to the black-blood image space using the Elastix tool [15]. For the registration of the sequences, a Region Of Interest (ROI) around the artery in black-blood was used. This ROI was obtained semi-automatically by uniformly growing an extracted carotid artery centerline, which requires three marked seed points at the common, internal and external parts of the artery [15]. Then calcification was manually delineated in every consecutive slice using an annotation tool developed in Mevislab (MeVisLab, MeVis Medical Solutions AG). Fourth, the total volume of calcification was calculated by counting the number of voxels within the annotated areas and multiplying this by the voxel volume (Fig. 1). This provided volumes of calcification in cubic millimeters.

At study entry, all participants were interviewed and a history of stroke was assessed. Moreover, after enrollment, all participants are continuously followed for the occurrence of stroke [16]. All potential stroke events were reviewed by research physicians and verified by an experienced stroke neurologist [17]. At the time of CT scan, 38 participants had suffered a prior stroke [16].

Due to skewed distributions of the calcification data, we used natural log (Ln) transformed values after we added 1.0 mm³ to the non-transformed data in order to deal with calcification scores of zero (Ln (calcification volume +1.0 mm³)) [16]. Our analysis strategy consisted of four steps. First, we investigated the correlation of CT-based calcification volumes with CMR-based calcification volumes using Spearman’s correlation coefficient. Second, we used linear regression to assess the relation between CT-based and CMR-based calcification volumes while adjusting for the time interval between the scans. Given the substantial time interval between the CT and CMR examinations, we furthermore performed a sensitivity analysis in which we analyzed the correlation between CT-based and CMR-based calcification volumes only for those persons with an interval equal or less than 3 years (n = 128). We performed post-hoc sensitivity analysis while adjusting for CT-scanner type also.

Third, we assessed the agreement between CT-based and CMR-based calcification volumes using a Bland-Altman analysis. Fourth, as a proof-of-principle, we investigated the association of CT-based and CMR-based calcification volumes (per 1-SD increase) related with a history of stroke using logistic regression while adjusting for age, sex and the time interval between CT and CMR, and studied whether the results were comparable for both modalities All analyses were carried out using IBM SPSS Statistics version 21 (International Business Machines Corporation, Armonk, New York).