Macro- and microvascular contributions to cerebral structural alterations in patients with asymptomatic carotid artery stenosis

Abstract

Atherosclerosis can underly internal carotid artery stenosis (ICAS), a major risk factor for ischemic stroke, as well as small vessel disease (SVD). This study aimed to investigate hemodynamics and structural alterations associated with SVD in ICAS patients. 28 patients with unilateral asymptomatic ICAS and 30 age-matched controls underwent structural (T1-/T2-weighted and diffusion tensor imaging [DTI]) and hemodynamic (pseudo-continuous arterial spin labeling and dynamic susceptibility contrast) magnetic resonance imaging. SVD-related alterations were assessed using free water (FW), FW-corrected DTI, and peak-width of skeletonized mean diffusivity (PSMD). Furthermore, cortical thickness, cerebral blood flow (CBF), and capillary transit time heterogeneity (CTH) were analyzed. Ipsilateral to the stenosis, cortical thickness was significantly decreased in the posterior dorsal cingulate cortex (p = 0.024) and temporal pole (p = 0.028). ICAS patients exhibited elevated PSMD (p = 0.005), FW (p < 0.001), and contralateral alterations in FW-corrected DTI metrics. We found significantly lateralized CBF (p = 0.011) and a tendency for lateralized CTH (p = 0.067) in the white matter (WM) related to ICAS. Elevated PSMD and FW may indicate a link between SVD and WM changes. Contralateral alterations were seen in FW-corrected DTI, whereas hemodynamic and cortical changes were mainly ipsilateral, suggesting SVD might influence global brain changes concurrent with ICAS-related hemodynamic alterations.

Keywords: Asymptomatic internal carotid artery stenosis; arterial spin labeling; cerebrovascular disease; diffusion tensor imaging; small vessel disease.

Figure 1.

Processing overview. The MRI data underwent processing using different software applications. Following DTI preprocessing, PSMD was computed based on the eddy-current and motion-corrected images. WMH quantification was performed in the individual space using FLAIR images. All other maps were subjected to non-linear coregistration to MNI space using respective pipelines. To investigate ICAS-associated changes on group level, the images of patients with left-sided stenosis were flipped to the right. Further analysis was conducted within the skeleton (for DTI indices) or within a WM mask, which was segmented based on the T1-weighted images using a threshold of 0.9 for the hemodynamic parameters (CTH, CBF). Additional regional analysis was carried out for cortical thickness and significant DTI indices to determine their specific spatial localization within the brain.

Figure 2.

Significant TBSS results for group comparison of DTI indices. Top row: significant results of the group-wise comparison of standard AD (a) and FW-corrected ADt (b). Bottom row: significantly higher standard MD (c) and FW (d) in patients than controls after correction for age and sex. For display, the presented voxels are magnified using tbss_fill, which creates the bold red framing around the significant voxels (p < 0.05). AD and MD present widespread alterations involving the whole skeleton, while changes in ADt and FW are more restricted mainly to the corpus callosum and the contralateral hemisphere. There is some overlap with ADt in regions exhibiting significantly higher FW, but the alterations in ADt are more extensively distributed. Note: To specifically address ICAS-related changes in the ipsilateral (ipsi) compared to the contralateral hemisphere, data of patients with left-sided stenosis were flipped.

Figure 3.

Skeleton-based whole-brain analysis of WM microstructure. Global averages of diffusion measures were assessed within the study-specific WM skeleton, which was obtained during the TBSS processing. Boxes illustrate data of controls or patients, with the center line representing the median and the bottom and top lines indicating the 25th and 75th percentiles, respectively. The whiskers indicate the range of data points not considered outliers, while outliers are shown using the ‘+' symbol. Outliers are defined as data points that are outside 1.5 times of the interquartile range from the upper or lower boundary of the box. Significance of group comparisons is indicated by p-values below the panels. The whole-brain analysis of the DTI indices revealed a significant increase in FW levels among patients (p < 0.001) and increased PSMD (p = 0.005) in patients.

Figure 4.

WM hemodynamics. Box plots of altered hemodynamic patterns for controls and patients. Boxes present data of controls or patients, with the center line representing the median, the bottom and top lines indicating the 25th and 75th percentiles, respectively. The whiskers display the range of data points not considered outliers, while outliers are shown using the ‘+' symbol. Outliers are defined as data points which are 1.5 times of the interquartile range from the upper or lower part of the box. To assess the hemodynamic situation, CBF, addressing perfusion, and CTH, presenting capillary flow heterogeneity, were analyzed within WM using a WM mask, segmented individually for each participant. The lateralization of these parameters depicts the overall change in WM perfusion in percent. CTH lateralization was higher in patients and elevated in the hemisphere ipsilateral to the stenosis. CBF was significantly lower in the hemisphere ipsilateral to the stenosis in patients.

Figure 5.

Partial correlations of whole-brain structural and hemodynamic parameters. Correlation coefficients of asymmetric flow pattern, assessed by lateralization of CBF and CTH, and structural parameters for controls (left) and patients (right). We utilized the mean values of FW-corrected DTI parameters within the whole-brain WM skeleton for our correlations, aiming to assess the potential impact of perfusion lateralization on overall brain structure. DTI indices exhibit strong intercorrelation, especially FW shows significant correlation with all FW-corrected DTI indices. In the control group, FW is significantly correlated solely to FAt, which might indicate that FAt is sensitive to variations in FW content, even in the absence of disease. CBF lateralization in WM showed its highest correlation with ADt in patients (r² = 0.30; p = 0.13), and a medium association to CTH lateralization (controls/patients r² = −0.41/−0.09; p = 0.08/0.27). CTH lateralization in WM presented little correlation regarding whole-brain structural parameters, the strongest being cortical thickness in patients (controls/patients: r² = −0.24/−0.35; p = 0.22/0.19).