Quantifying Intracranial Plaque Permeability with Dynamic Contrast-Enhanced MRI: A Pilot Study

Patient Recruitment

Institutional review board approval was obtained for a prospective, Health Insurance Portability and Accountability Act–compliant study of symptomatic patients presenting with ischemic stroke or transient ischemic attack secondary to ICAD with >50% stenosis and plaques involving the internal carotid artery, A1-A2 anterior cerebral, M1-M2 middle cerebral, and P1-P2 posterior cerebral arteries, or basilar artery (Table 1). When attributable to the downstream vascular distribution of a single ICAD plaque, “ischemic stroke” was defined as hyperintensity findings on DWI and “TIA” was defined as neurologic deficits that resolved in <24 hours. Patients were identified and recruited for this study at Northwestern University from March 2013 to May 2015, after receiving a standard clinical head and neck MRI/MRA evaluation, including 3D TOF and DWI sequences. Patients provided consent based on a willingness to participate in a longitudinal study and the ability to undergo a research MR imaging examination within 30 days of the ischemic event.

Recruited patients underwent high-resolution, vessel wall imaging with 3T BBMRI of the intracranial vasculature. In addition, the ICAD stenosis was evaluated with DCE-MR imaging for the purpose of kinetic modeling of permeability (or contrast uptake) into the plaque. Major patient exclusion criteria included complete vessel occlusions, gross patient motion artifacts, susceptibility artifacts from implants, >50% stenosis of the cervical vasculature or tandem intracranial stenoses (via MRA/CTA or carotid Doppler sonography), cardioembolic risk profile including atrial fibrillation, and standard contraindications to MR imaging (pacemaker, claustrophobia, pregnancy, contrast allergy, or renal insufficiency). We further studied patient demographics, atherosclerotic risk factors, relevant medical management, and clinical presentations using Northwestern University's electronic medical records.

Imaging Protocol

All patients enrolled in our study were scanned on 3T (Magnetom Trio or Skyra; Siemens, Erlangen, Germany) MR imaging scanners. A 3D TOF MRA sequence was repeated to localize the ICAD plaque in the vessel of interest. The DCE-MR imaging volume was placed to cover the entire segment of the diseased intracranial vessel (Fig 1) with the axis of the vessel aligning with the through-plane direction and in-plane images containing perpendicular vessel cross-sections. Plaque permeability was measured with a standard DCE-MR imaging protocol using a multiphase 3D gradient recalled-echo (GRE)-based pulse sequence. Dynamic volumetric T1-weighted images were acquired approximately every 35 seconds following contrast injection for approximately 10 minutes with the following parameters: flip angle = 10°, TR/TE = 8.7/1.3 ms, matrix = 384 × 384, FOV = 190–220 mm, and 12 partitions placed to cover the plaque, resulting in voxel dimensions of 0.5 × 0.5 × 2.0 mm. A single dose (0.1 mmol/kg) of T1-shortening gadolinium contrast (gadopentetate dimeglumine, Magnevist; Bayer HealthCare Pharmaceuticals, Wayne, New Jersey) was injected at a rate of 4 mL/s during the DCE acquisition. Precontrast T1 values (T₁₀) of the tissue were determined using a multi-flip angle routine (α = 5°, 15°, 25°, 45°) to fit the spoiled gradient-echo signal equation:^13,14

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Fig 1.

Vessel wall imaging data in a 63-year-old man with symptomatic severe left MCA stenosis resulting in perforator thromboembolic infarcts as seen on 3D TOF MRA MIP and DWI (A). 3D BBMRI with postcontrast T1 SPACE imaging demonstrates plaque enhancement in an axial and coronal cross-sections of the MCA (B). A manual ROI isolates the enhancing plaque on the postcontrast T1 SPACE image (C, right, yellow ROI on the plaque inset). Kinetic modeling of contrast uptake into the plaque was performed by using DCE-MR imaging in the coregistered plaque ROI, and K^trans values were calculated in each voxel (C, left). Normal control values were calculated in a region of normal white matter (red dotted ROI in C). The mean enhancement signal (white diamonds) and fitted Tofts curve (yellow) are shown from the plaque ROI (D). Note the difference in enhancement relative to healthy brain tissue (D, red ROI and red curve/squares).

3D isotropic, high-resolution BBMRI was performed with T1-weighted TSE sequences, acquired before and immediately after the DCE acquisition (ie, within 20 minutes of the gadolinium injection). A 3D variable flip angle TSE (T1 sampling perfection with application-optimized contrasts by using different flip angle evolution [SPACE]; Siemens) pulse sequence^5,15 was performed before and after contrast injection with the following parameters: FOV = 165 mm, TR/TE = 800/22 ms, integrated parallel acquisition technique factor = 2, 104 partitions, bandwidth = 372 Hz/pixel, turbo factor = 30, scan time ∼ 8 minutes, voxel volume = 0.5 × 0.5 × 0.6 mm.

Permeability Modeling

The permeability-limited Modified Tofts Model¹⁶ quantifies the kinetics of a tracer leaking through a semipermeable membrane with the following relationship: with K^trans dictating the tracer transfer rate from the intravascular into the extracellular extravascular space (V_L) with units of minute⁻¹; K_ep = K^trans/V_L in units of minute⁻¹ describing the ratio of the transfer rate (K^trans) to the fractional volume of tracer in the V_L; C_p(t), the intravascular tracer concentration; and V_p, the fractional plasma volume for each voxel. C(t) is measured adjacent to the patent lumen of the stenotic vessel wall. A Levenberg-Marquardt algorithm was implemented in-house by using a commercially available software prototyping package (Matlab, Version 2014; MathWorks, Natick, Massachusetts) to find the K^trans, V_L, and V_p in Equation 2 that best fit the measured signal C(t). Acquisition of the enhancement curve peak is required for an accurate measurement of V_L and may require imaging times greater than 10 minutes. While V_L may be related to plaque enhancement, it does not affect the wash-in phase of the enhancement curve¹⁷; thus, we restricted our analysis to K^trans and V_p values as in prior kinetic modeling analyses.^7,9

Data Analysis and Imaging Evaluation

Both DCE and T1 SPACE images were evaluated as a postprocessing step by separate, independent operators who were blinded to both clinical history and the results of complementary image analysis.

T1 SPACE images were analyzed on a Leonardo workstation (Siemens) by a neuroradiologist with >10 years' experience (A.H.E). Measurements included relative postgadolinium plaque enhancement between pre- and postcontrast imaging, referred to as intraplaque enhancement (IPE), as well as the presence of precontrast signal intensity (SI), referred to as intraplaque hyperintensity (IPH). ROIs were drawn in one section at the site of maximal vessel stenosis, and the mean SI was recorded. ROIs were matched in size and location in the precontrast T1 SPACE dataset. IPE was calculated as SI_post − SI_pre / SI_pre. Both SI_post and SI_pre were first normalized to the SI of normal-appearing white matter (NAWM). IPH was measured as the ratio of precontrast plaque SI to extraocular muscle SI.

DCE images were motion-corrected by using the Statistical Parametric Mapping (SPM8 (http://www.fil.ion.ucl.ac.uk/spm/software/spm12) software package in Matlab (R2014a). The ROI for contrast kinetic analysis was matched as closely as possible to the ROI used for IPE analysis by first coregistering the T1 SPACE postcontrast ROI volumes to DCE-MR imaging volumes and then applying pixel-by-pixel DCE modeling in the section containing maximal plaque enhancement on the coregistered T1 SPACE image. ROIs were drawn in Matlab by a trained operator with >10 years' experience (P.V.). We evaluated the permeability of the choroid plexus and NAWM^18⇓–20 in the same patients to provide an internal reference for our plaque contrast kinetic parameters.

Statistical Analysis

We compared quantitative DCE-MR imaging parameters in plaques against the aforementioned independent controls (white matter and choroid plexus) and neuroanatomic structures with differential permeability characteristics.^{18,19,21⇓–23} Mean values were compared by using a Student t test with statistical significance defined at the 5% level (P < .05).

A linear regression analysis was preformed to compare DCE parameters (K^trans and V_p) as well as IPH and IPE ratios with the time from symptom onset (in days). Time from symptom onset was calculated as the number of days until DCE and T1 SPACE MR imaging studies were performed at our research institution. This analysis was conducted to evaluate the difference in associativity with time between the 2 imaging markers.

Finally, DCE parameters were compared with IPH and IPE ratios in all plaques by using linear regression to evaluate their interdependent relationships. All statistical analyses were conducted by using built-in statistical software in Matlab. Confidence intervals were set at 95%, and statistical significance was defined at the 5% level (P < .05).