Severe asymptomatic stenosis of the internal carotid artery (ICA) leads to increased incidence of mild cognitive impairment (MCI) likely through silent embolic infarcts and/or chronic hypoperfusion, but the brain dysfunction is poorly understood and difficult to diagnose. Thirty cognitively intact subjects with asymptomatic, severe (≥ 70%), unilateral stenosis of the ICA were compared with 30 healthy controls, matched for age, sex, cardiovascular risk factors and education level, on a battery of neuropsychiatric tests, voxel-based morphometry of magnetic resonance imaging (MRI), diffusion tensor imaging and brain-wise, seed-based analysis of resting-state functional MRI. Multivariate regression models and multivariate pattern classification (support vector machines) were computed to assess the relationship between connectivity measures and neurocognitive performance. The patients had worse dizziness scores and poorer verbal memory, executive function and complex visuo-spatial performance than controls. Twelve out of the 30 patients (40%) were considered to have MCI. Nonetheless, the leukoaraiosis Sheltens scores, hippocampal and brain volumes were not different between groups. Their whole-brain mean fractional anisotropy (FA) was significantly reduced and regional functional connectivity (Fc) was significantly impaired in the dorsal attention network (DAN), frontoparietal network, sensorimotor network and default mode network. In particular, the Fc strength at the insula of the DAN and the mean FA were linearly related with attention performance and dizziness severity, respectively. The multivariate pattern classification gave over 90% predictive accuracy of individuals with MCI or severe dizziness. Cognitive decline in stroke-free individuals with severe carotid stenosis may arise from nonselective widespread disconnections of long-range, predominantly interhemispheric non-hippocampal pathways. Connectivity measures may serve as both predictors for cases at risk and therapeutic targets for mitigating vascular cognitive impairment.

Cortical thinning is a potentially important biomarker, but the pathophysiology in cerebrovascular disease is unknown. We investigated the association between regional cortical blood flow and regional cortical thickness in patients with asymptomatic unilateral high-grade internal carotid artery disease without stroke. Twenty-nine patients underwent high resolution anatomical and single-delay, pseudocontinuous arterial spin labeling magnetic resonance imaging with partial volume correction to assess gray matter baseline flow. Cortical thickness was estimated using Freesurfer software, followed by co-registration onto each patient's cerebral blood flow image space. Paired t-tests assessed regional cerebral blood flow in motor cortex (supplied by the carotid artery) and visual cortex (indirectly supplied by the carotid) on the occluded and unoccluded side. Pearson correlations were calculated between cortical thickness and regional cerebral blood flow, along with age, hypertension, diabetes and white matter hyperintensity volume. Multiple regression and generalized estimating equation were used to predict cortical thickness bilaterally and in each hemisphere separately. Cortical blood flow correlated with thickness in motor cortex bilaterally (p = 0.0002), and in the occluded and unoccluded sides individually; age (p = 0.002) was also a predictor of cortical thickness in the motor cortex. None of the variables predicted cortical thickness in visual cortex. Blood flow was significantly lower on the occluded versus unoccluded side in the motor cortex (p<0.0001) and in the visual cortex (p = 0.018). On average, cortex was thinner on the side of occlusion in motor but not in visual cortex. The association between cortical blood flow and cortical thickness in carotid arterial territory with greater thinning on the side of the carotid occlusion suggests that altered cerebral hemodynamics is a factor in cortical thinning.

Moyamoya is a cerebrovascular disorder characterized by progressive stenosis of the intracranial internal carotid arteries. There are two forms: Disease and Syndrome, with each characterized by the sub-population it affects. Moyamoya syndrome (MMS) is more prominent in adults in their 20's-40's, and is often associated with autoimmune diseases. Currently, there are no surgical models for inducing moyamoya syndrome, so our aim was to develop a new animal model to study this relatively unknown cerebrovascular disease. Here, we demonstrate a new surgical technique termed internal carotid artery stenosis (ICAS), to mimic MMS using micro-coils on the proximal ICA. We tested for Moyamoya-like vasculopathies by fluorescently labelling the mouse cerebrovasculature with Di I for visualization and analysis of vessel diameter at the distal ICA and anastomoses on the cortical surface. Results show a significant narrowing of the distal ICA and anterior cerebral artery (ACA) in the Circle of Willis, as observed in humans. There is also a significant decrease in the number of anastomoses between the middle cerebral artery (MCA) and the ACA in the watershed region of the cortex. While further characterization is needed, this ICAS model can be applied to transgenic mice displaying co-morbidities as observed within the Moyamoya syndrome population, allowing a better understanding of the disease and development of novel treatments.

Carotid artery stenting (CAS) has been advocated as an alternative to redo surgery for the treatment of post-carotid endarterectomy (CEA) stenosis. This study analyzed the efficacy of CAS for post-CEA restenosis, focusing on an analysis of technical and anatomical predictive factors for in-stent restenosis.

Early detection of asymptomatic carotid stenosis may help identifying individuals at risk of stroke. We explore a new method based on laser Doppler vibrometry (LDV) which could allow the non-contact detection of stenosis from neck skin vibrations due to stenosis-induced flow disturbances. Experimental fluid dynamical tests were performed with water on a severely stenosed patient-specific carotid bifurcation model. Measurements were taken under various physiological flow regimes both in a compliant and stiff-walled version of the model, at 1 to 4 diameters downstream from the stenosis. An inter-arterial pressure catheter was positioned as reference. Increasing flow led to corresponding increase in power spectral density (PSD) of pressure and LDV recordings in the 0-500 Hz range. The stiff model lead to higher PSD. PSD of the LDV signal was less dependent on the downstream measurement location than pressure. The strength of the association between PSD and flow level, model material and measuring location was highest in the 0-50 Hz range, however useful information was found up to 200 Hz. This proof-of-concept suggests that LDV has the potential to detect stenosis-induced disturbed flow. Further computational and clinical validation studies are ongoing to assess the sensitivity and specificity of the technique for clinical screening.

To evaluated the changes in choroidal vasculature in patients with ocular ischemic syndrome (OIS) and in the ipsilateral eyes of patients with symptomatic carotid artery stenosis (CAS).

Carotid plaque features assessed using B-mode ultrasound can be useful for the prediction of cerebrovascular symptoms. Therefore, the aim of this retrospective study was to determine the ability of ultrasound B-mode imaging to differentiate between carotid plaques causing less than 50% stenosis in symptomatic and asymptomatic patients. A dataset of 1,593 patients with carotid disease who underwent carotid ultrasound between 2016 and 2021 was evaluated retrospectively between January and April of 2022. A total of 107 carotid plaques from 35 symptomatic and 52 asymptomatic patients causing low-grade stenosis on B-mode images were included in the analysis. Chi-square, independent t-test and Mann-Whitney U test were used to compare the variables. There was a significant association between hypertension and the presence of cerebrovascular symptoms (p = 0.01). Predominantly hypoechoic and hyperechoic carotid plaque were significantly associated with the presence and absence of cerebrovascular symptoms, respectively (predominantly hypoechoic: p = 0.01; predominantly hyperechoic: p = 0.02). Surface irregularity was significantly associated with the presence of cerebrovascular symptoms (p = 0.02). There is was a significant difference in the carotid plaque length and area between the symptomatic and asymptomatic patients (plaque length: symptomatic median 9 mm, interquartile range [IQR] 6 mm; asymptomatic median 6 mm, IQR 4.5 mm, p = 0.01; plaque area: symptomatic median 24 mm, IQR 30 mm; asymptomatic median 14 mm, IQR 17 mm, p = 0.01); however, this difference was not significant for plaque thickness (p = 0.55), or common carotid artery intima-media thickness (p = 0.7). Our findings indicate that hypertension patients with predominantly hypoechoic carotid plaques and plaques with an irregular surface are associated with the presence of cerebrovascular symptoms. In addition, the carotid plaques in symptomatic patients were longer and larger compared to asymptomatic patients.

The cerebral and retinal circulation systems are developmentally, anatomically, and physiologically interconnected. Thus, we hypothesized that hypoperfusion due to atherosclerotic stenosis of the internal carotid artery (ICA) can result in disturbances of both cerebral and retinal microcirculations. We aimed to characterize parameters indicating cerebrovascular reactivity (CVR) and retinal microvascular density in patients with ICA stenosis, and assess if there is correlation between them.

Bilateral carotid artery stenosis (BCAS) is one experimental model of vascular dementia thought to preferentially impact brain white matter. Indeed, few studies report hippocampal and cortical pathology prior to 30 days post-stenosis; though it is unclear whether those studies examined regions outside the white matter. Since changes in the blood-brain barrier (BBB) permeability precede more overt brain pathology in various diseases, we hypothesized that changes within the BBB and/or BBB-associated extracellular matrix (ECM) could occur earlier after BCAS in the hippocampus, cortex and striatum and be a precursor of longer term pathology. Here, C57Bl/6 mice underwent BCAS or sham surgeries and changes in the BBB and ECM were analyzed by collagen IV (vascular basement membrane component), α5 integrin (marker of endothelial activation), claudin-5 and occludin (tight junction proteins), Evans blue (permeability marker), Ki-67 (cell proliferation marker), and GFAP and CD11b (glial cell markers) immunohistochemistry after 14 days. Significant changes in markers of cerebrovascular integrity and glial activation were detected, not only in the striatum, but also in the hippocampus and cortex. In conclusion, this study demonstrates for the first time that changes in the BBB/ECM occur shortly after BCAS and within multiple brain regions and suggests such changes might underlie the gradual development of BCAS non-white matter pathology.

Recently, we have shown that intraplaque mast cell numbers are associated with atherosclerotic plaque vulnerability and with future cardiovascular events, which renders inhibition of mast cell activation of interest for future therapeutic interventions. However, the endogenous triggers that activate mast cells during the progression and destabilization of atherosclerotic lesions remain unidentified. Mast cells can be activated by immunoglobulins and in the present study, we aimed to establish whether specific immunoglobulins in plasma of patients scheduled for carotid endarterectomy were related to (activated) intraplaque mast cell numbers and plasma tryptase levels. In addition, the levels were related to other vulnerable plaque characteristics and baseline clinical data.

Complications due to brain edema and breakdown of blood brain barrier are an important factor affecting the treatment effects of patients with severe carotid stenosis. In this study, we investigated the protective effects of ischemic postconditioning on brain edema and disruption of blood brain barrier via establishing rat model of hypoperfusion due to severe carotid stenosis.

Perfusion weighted imaging (PWI) is inherently unreliable in patients with severe perfusion abnormalities. We compared the diagnostic accuracy of a novel index of microvascular flow-patterns, so-called capillary transit time heterogeneity (CTH) to that of the commonly used delay parameter Tmax in patients with bilateral high grade internal carotid artery stenosis (ICAS).

Percutaneous carotid artery stenting (CAS) became a widely used procedure in patients with symptomatic and asymptomatic carotid artery stenosis. However its role compared to carotid endarterectomy (CAD) remains questioned. We analysed the safety of carotid artery stenting program of a prospective CAS register program of a tertiary teaching hospital.

Carotid artery occlusive disease gradually develops over time, eventually leading to cerebral infarction and high mortality rate. Animal models replicating cerebral infarction resulting from carotid artery occlusive disease have thus been developed to test potential novel treatments, which could be subsequently administered clinically.

Atherosclerotic lesions that critically narrow the artery can necessitate an angioplasty and stent implantation. Long-term therapeutic effects, however, are limited by excessive arterial remodeling. We here employed a miniaturized nitinol-stent coated with star-shaped polyethylenglycole (star-PEG), and evaluated its bio-functionalization with RGD and CXCL1 for improving in-stent stenosis after implantation into carotid arteries of mice. Nitinol foils or stents (bare metal) were coated with star-PEG, and bio-functionalized with RGD, or RGD/CXCL1. Cell adhesion to star-PEG-coated nitinol foils was unaltered or reduced, whereas bio-functionalization with RGD but foremost RGD/CXCL1 increased adhesion of early angiogenic outgrowth cells (EOCs) and endothelial cells but not smooth muscle cells when compared with bare metal foils. Stimulation of cells with RGD/CXCL1 furthermore increased the proliferation of EOCs. In vivo, bio-functionalization with RGD/CXCL1 significantly reduced neointima formation and thrombus formation, and increased re-endothelialization in apoE-/- carotid arteries compared with bare-metal nitinol stents, star-PEG-coated stents, and stents bio-functionalized with RGD only. Bio-functionalization of star-PEG-coated nitinol-stents with RGD/CXCL1 reduced in-stent neointima formation. By supporting the adhesion and proliferation of endothelial progenitor cells, RGD/CXCL1 coating of stents may help to accelerate endothelial repair after stent implantation, and thus may harbor the potential to limit the complication of in-stent restenosis in clinical approaches.

Atherosclerosis is responsible for the death of thousands of Americans each year. The carotid constriction model of plaque development has recently been presented as a model for unstable plaque formation in mice. In this study we 1) validate ultrasound biomicroscopy (UBM) for the determination of carotid plaque size, percent stenosis, and plaque development in live animals, 2) determine the sensitivity of UBM in detecting changes in blood flow induced by carotid constriction and 3) test whether plaque formation can be predicted from blood flow parameters measured by UBM. Carotid plaques were induced by surgical constriction in Apo E⁻/⁻ mice. Arteries were imaged bi-weekly by UBM, at which time PW-Doppler measurements of proximal blood flow, as well as plaque length and percent stenosis were determined. Histology was performed 9 weeks post surgery. When compared to whole mount post-mortem measurements, UBM accurately reported carotid plaque length. Percent stenosis, based on transverse B-mode UBM measurements, correlated well with that calculated from histological sections. PW-Doppler revealed that constriction reduced maximum systolic velocity (v(max)) and duration of the systolic velocity peak (t(s)/t(t)). Pre-plaque (2 week post-surgery) PW-Doppler parameters (v(max) and t(s)/t(t)) were correlated with plaque length at 9 weeks, and were predictive of plaque formation. Correlation of initiating PW-Doppler parameters (v(max) and t(s)/t(t)) with resulting plaque length established the degree of flow disturbance required for subsequent plaque development and demonstrated its power for predicting plaque development.

Carotid angioplasty and stenting (CAS) may currently be recommended especially in younger patients with a high-grade carotid artery stenosis. However, evidence is accumulating that in-stent restenosis (ISR) could be an important factor endangering the long-term efficacy of CAS. The aim of this study was to investigate the influence of inflammatory serum markers and procedure-related factors on ISR as diagnosed with duplex sonography.

Polymorphonuclear neutrophils (PMN) in atherosclerotic plaques have been identified only recently, and their contribution to plaque development is not yet fully understood. In this study, production of elastase, interleukin (IL)-8 and vascular endothelial growth factor (VEGF) by PMN was investigated in subjects with carotid stenosis undergoing carotid endarterectomy (CEA).

Many recent trials have investigated the long-term efficacy and safety of endarterectomy versus stenting in treating patients with carotid artery stenosis. We aimed to determine the long-term comparative efficacy and safety of both procedures by pooling this evidence in a meta-analysis.

Quantitative T2'-mapping detects regional changes of the relation of oxygenated and deoxygenated hemoglobin (Hb) by using their different magnetic properties in gradient echo imaging and might therefore be a surrogate marker of increased oxygen extraction fraction (OEF) in cerebral hypoperfusion. Since elevations of cerebral blood volume (CBV) with consecutive accumulation of Hb might also increase the fraction of deoxygenated Hb and, through this, decrease the T2'-values in these patients we evaluated the relationship between T2'-values and CBV in patients with unilateral high-grade large-artery stenosis.