Simultaneous Non-contrast Angiography and intraPlaque hemorrhage (SNAP) imaging for carotid atherosclerotic disease evaluation Authors:

A Simultaneous Non-contrast Angiography and intraPlaque hemorrhage (SNAP) MR imaging technique was proposed to detect both luminal stenosis and hemorrhage in atherosclerosis patients in a single scan. 13 patients with diagnosed carotid atherosclerotic plaque were recruited after informed consent. All scans were performed on a 3T MR imaging system with SNAP, 2D time-offlight (TOF) and magnetization-prepared 3D rapid acquisition gradient echo (MPRAGE) sequences. The SNAP sequence utilized a phase sensitive acquisition, and was designed to provide positive signals corresponding to intraplaque hemorrhage (IPH) and negative signals corresponding to lumen. SNAP images were compared to TOF images to validate lumen area measurements using linear mixed models and the intraclass correlation coefficient (ICC). IPH identification accuracy was evaluated by comparing to MP-RAGE images using Cohen’s Kappa. Diagnostic quality SNAP images were generated from all subjects. Quantitatively, the lumen area measurements by SNAP were strongly correlated (ICC=0.96, p<0.001) with those measured by TOF. For IPH detection, strong agreement (κ=0.82, p<0.001) was also identified between SNAP and MPRAGE images. The SNAP technique was proposed and validated to reliably detect in a single acquisition both luminal size and intraplaque hemorrhage in the patients with carotid atherosclerosis. Introduction Luminal stenosis remains the current clinical standard for evaluating stroke risk due to carotid disease (1). Although contrast-enhanced MR angiography (MRA) has been shown to provide highly accurate stenosis measurements in carotid artery disease (2), the risk of triggering nephrogenic systemic fibrosis (3) in patients with impaired renal function, limits the application of contrast-enhanced MRA in clinical environments. Additionally, the requirement of acquiring images within the first-pass timeframe also limits the spatial resolution and signal-tonoise ratio (SNR) that can be achieved by such techniques. To overcome these issues, there have been clinical interests in using non-contrast enhanced MRA techniques as alternative approaches for luminal stenosis measurements (4-7). Intraplaque hemorrhage (IPH) identified in the atherosclerotic plaque is also strongly associated with increased risks of clinical events (8-10) as well as plaque progression (11-12). IPH has also been suggested to be a potentially important factor in surgical planning (13). A number of MR imaging techniques have been developed to detect IPH in atherosclerotic plaques (14-16). All take advantage of the short T1 relaxation times of IPH components, which lead to hyperintensities on T1-weighted images. Among several of the options, the magnetization-prepared rapid acquisition gradient echo (MP-RAGE) technique was recently found to have the highest sensitivity and specificity (17). Given the established clinical importance of stenosis and the emerging interests in detecting IPH in patients at high risk of developing stroke, an efficient means for the assessment of both stenosis and IPH is desirable. The current MRA techniques cannot effectively visualize the vessel wall components; as a consequence, IPH information must now be separately acquired, at the expense of extra scanning time and with additional challenges arising from the need for image registration. These added technical challenges are substantial impediments to the integration of IPH imaging with MRA for carotid atherosclerosis evaluations. In this manuscript, we propose a Simultaneous Non-contrast Angiography and intraPlaque hemorrhage (SNAP) imaging technique that allows both MRA and IPH evaluations in the same acquisition. The SNAP technique is based on the previously reported Slab-selective Phase-sensitive Inversion-Recovery (SPI) sequence (18). Taking advantage of the phase-sensitive reconstruction (19) used in SPI, the SNAP sequence generates images with negative signal corresponding to MRA and positive signal corresponding to IPH. By displaying only the negative signals, a non-contrast MR angiogram is rendered with no contamination from background tissues. Displaying the positive signals, on the other hand, yields a highly T1-weighted image suitable for IPH detection. To test this concept, we sought to validate the ability of SNAP to measure lumen area and detect IPH by comparing with previously established time of flight (TOF) and MP-RAGE techniques. Materials and Methods Pulse sequence and optimization The pulse sequence of SNAP is shown in Fig. 1 – each arrow represents a gradient echo acquisition with flip angle (FA) of α or 5°. 5° is the default value specified by the scanner for phase sensitive reconstruction acquisition. A linear k-space filling scheme was used so that the central α pulse of the pulse train corresponded to the inversion time (TI) when the center of k-space was acquired. Further details are given in Fig.1. Assuming the magnetization of static tissue before each IR has already reached its steady state Mss, the magnetization before the first α pulse will be, ) 1 ( ) / exp( ) ( ) ( 1 0 0 T T M M M T M gap ss gap z      Right before the j (j>1) α pulse, the signal will be, ) 2 ( cos 1 ) cos ( 1 ) 1 ( ) cos )( ( ) ( 1 1 1 1 0 1 1     E E E M E T M j M j j gap z z          Where E1=exp(-TR/T1). Assume that the (N+1) th RF pulse corresponds to the TI time, because the linear k-space filling scheme is used, there will be 2N+1 α pulses and 2N+1 low FA (5° here) reference pulses. For simplicity reasons, 5° will be used throughout the following analysis although other values may also be used. The signal level before the first 5o RF pulse will be, ) 3 ( ) ) 2 2 (( ) 1 ( ) ( 0 g z g z E N M E M PS M        Where PS indicates the time when the low flip angle pulse train starts. The corresponding relaxation can be given as: Eg=exp(-(Tex+Tgap)/T1). The signal before the j (j>1) 5o RF pulse will be, ) 4 ( 5 cos 1 ) 5 cos ( 1 ) 1 ( ) 5 cos )( ( ) ( 1 1 1 1 0 1 1 5             E E E M E PS M j M j j z z After all 2N+1 5o RF pulses are carried out and a Tex delay time, the signal right before the next IR pulse would give the steady state magnetization Mss, i.e., ) 5 ( ) ) 2 2 (( ) 1 ( 5 0 e z e ss E N M E M M      Where Ee=exp(-Tex/T1). Combining Eq. [1-5], the value of Mss can be obtained. Due to its complexity, the value of Mss for each individual tissue won’t be solved analytically here. From Eq. [2], at the selected inversion time (TI), the signal level for IPH, vessel wall and blood can be written as, ) 6 ( ) / exp( ) cos 1 ) cos ( 1 ) 1 ( ) cos )( ( ( ) ( * 2 1 1 1 0 1 T TE E E E M E T M TI M N N gap z z           After solving numerically the value of Mss from Eq. [1-5] and plugging Eq. [1] into Eq. [6], the signal level of static tissue components, IPH and wall, can be computed. Since the imaging parameters were optimized to make sure only fresh blood is imaged, the blood signal can also be calculated using Eq. [6] by simply setting the Mz = 1 before each IR. The aim of the optimization was to select proper TI and flip angle α to maximize IPH-wall and wall-lumen contrasts at the same time. The following equation was used as the aim of the optimization, ) 7 ( lumen wall wall IPH C C      Where, CIPH-wall is the magnetization difference between IPH and wall at the time of TI and Cwall-lumen is the difference between wall and lumen. To maximize ξ, TI values between 200-1000ms and FA between 5o-25o were attempted. The parameter combination with the maximum ξ was selected as the optimized parameter for the following experiments. In the simulation programmed in Matlab (R2010a, Mathworks, Natick, MA), the T1 relaxation times used for different tissues were: IPH 500ms (16), wall 1115ms (20) and blood 1550ms (20); The T2 * values used were: IPH 15ms (21), wall 20ms (20) and blood 275ms. Based on the current hardware/software settings, the minimum TR/TE values that can be achieved on the scanner were 10/4.8ms, Tgap and Tex were 20 and 5ms.