Inflammation and angiogenesis play major roles in carotid plaque vulnerability. The purpose of this study was to determine if grayscale features of carotid plaques are associated with histological markers for inflammation. Thirty-eight individuals completed a dedicated research carotid ultrasound exam prior to carotid endarterectomy. Grayscale analysis was performed on plaque images to measure plaque echogenicity (grayscale median [GSM] pixel brightness), plaque area, presence of discrete white areas [DWAs], and the percent of black area near the lumen on any one component of the plaque. Plaques with higher ultrasound GSM had greater percent calcification (p=0.013) on histopathology. Presence of an ultrasound DWA was associated with more plaque hemosiderin (p=0.0005) and inflammation (p=0.019) on histopathology examination. The percent of plaque black area in any one component was associated with a higher score for macroscopic ulceration (p=0.028). Ultrasound plaque characteristics (GSM, DWAs and Black areas) represent histopathological markers associated with plaque vulnerability.

Vascular cognitive decline may be caused by micro-emboli generated from carotid plaque instability. We have previously shown that maximum strain indices in carotid plaque were significantly correlated with cognitive function. In this paper, we examine these associations with a larger sample size, along with performance evaluation of these maximum strain indices to predict cognitive impairment. Ultrasound-based strain imaging and cognition assessment were conducted on 75 human subjects. Patients underwent one of two standardized cognitive test batteries, using either the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) or the National Institute of Neurological Disorder and Stroke-Canadian Stroke Network (NINDS-CSN) Vascular Cognitive Impairment Harmonization Standards (60-minute). Scores were standardized within each battery to allow these data to be combined across all participants. Radiofrequency signals for ultrasound strain imaging were acquired on the carotid arteries using either a Siemens Antares with a VFX 13-5 linear array transducer or a Siemens S2000 with a 18L6 linear array transducer. The same hierarchical block-matching motion tracking algorithm developed in our laboratory was utilized to estimate accumulated axial, lateral, and shear strain indices in carotid plaque with inclusion of adventitia regardless of the ultrasound system and transducer used. Associations between cognitive z-scores and maximum strain indices were examined using Pearson’s correlation coefficients. Maximum strain indices were also utilized to predict cognitive impairment using ROC analysis. All correlations between maximum strain indices and total cognition were statistically significant (p<0.05), indicating that these indices have good utility for predicting cognitive impairment. Maximum lateral strain indices provide an AUC of 0.85 for symptomatic patients, and 0.68 for asymptomatic patients. Our results demonstrate the important relationship of maximum strain indices and cognitive function, and the feasibility of using maximum strain indices to predict cognitive decline with inclusion of adventitia layer into the segmentation of plaque.

OBJECTIVE This article describes the use of ultrasound measurements of physical strain within carotid atherosclerotic plaques as a measure of instability and the potential for vascular cognitive decline, microemboli, and white matter changes. METHODS Asymptomatic patients with significant (> 60%) carotid artery stenosis were studied for dynamic measures of plaque instability, presence of microemboli, white matter changes, and vascular cognitive decline in comparison with normative controls and premorbid state. RESULTS Although classically asymptomatic, these patients showed vascular cognitive decline. The degree of strain instability measured within the atherosclerotic plaque directly predicted vascular cognitive decline in these patients thought previously to be asymptomatic according to classic criteria. Furthermore, 26% of patients showed microemboli, and patients had twice as much white matter hyperintensity as controls. CONCLUSIONS These data show that physical measures of plaque instability are possible through interpretation of ultrasound strain data during pulsation, which may be more clinically relevant than solely measuring degree of stenosis. The data also highlight the importance of understanding that the definition of symptoms should not be limited to motor, speech, and vision function but underscore the role of vascular cognitive decline in the pathophysiology of carotid atherosclerotic disease. Clinical trial registration no.: NCT02476396 (clinicaltrials.gov).

Higher local carotid artery strain has previously been shown to be a characteristic of unstable carotid plaques. These plaques may be characterized by microvascular changes that predispose to intraplaque hemorrhage, increasing the likelihood of embolization. Little is known however, about how these strain indices correspond with imaging markers of brain health and metrics of brain structure. White matter hyperintensities (WMHs), which are bright regions seen on T2-weighted brain MRI imaging, are postulated to result from cumulative ischemic vascular injury. Consequently, we hypothesized that plaques that are more prone to microvascular changes and embolization, represented by higher strain indices on ultrasound, would be associated with an increased amount of WMH lesion volume. This relationship would suggest not only emboli as a cause for the brain degenerative changes, but more importantly, a common microvascular etiology for large and small vessel contributions to this process. Subjects scheduled to undergo a carotid endarterectomy were recruited from a neurosurgery clinic. Prior to surgery, participating subjects underwent both ultrasound strain imaging and brain MRI scans as part of a larger clinical study on vascular health and cognition. A linear regression found that maximum absolute strain and peak to peak strain in the surgical side carotid artery were predictive of WMH burden. Furthermore, the occurrence of microembolic signals monitored using transcranial Doppler (TCD) ultrasound examinations also correlated with increasing lesion burden. It is becoming increasingly recognized that cognitive decline is often multifactorial in nature. One contributing extra-brain factor may be changes in the microvasculature that produce unstable carotid artery plaques. In this study, we have shown that higher strain indices in carotid artery plaques are significantly associated with an increased WMH burden, a marker of vascular mediated brain damage.

Vulnerability and instability in carotid artery plaque has been assessed based on strain variations using noninvasive ultrasound imaging. We previously demonstrated that carotid plaques with higher strain indices in a region of interest (ROI) correlated to patients with lower cognition, probably due to cerebrovascular emboli arising from these unstable plaques. This work attempts to characterize the strain distribution throughout the entire plaque region instead of being restricted to a single localized ROI. Multiple ROIs are selected within the entire plaque region, based on thresholds determined by the maximum and average strains in the entire plaque, enabling generation of additional relevant strain indices. Ultrasound strain imaging of carotid plaques, was performed on 60 human patients using an 18L6 transducer coupled to a Siemens Acuson S2000 system to acquire radiofrequency data over several cardiac cycles. Patients also underwent a battery of neuropsychological tests under a protocol based on National Institute of Neurological Disorders and Stroke and Canadian Stroke Network guidelines. Correlation of strain indices with composite cognitive index of executive function revealed a negative association relating high strain to poor cognition. Patients grouped into high and low cognition groups were then classified using these additional strain indices. One of our newer indices, namely the average L-1 norm with plaque (AL1NWP) presented with significantly improved correlation with executive function when compared to our previously reported maximum accumulated strain indices (MASI). An optimal combination of three of the new indices generated classifiers of patient cognition with an area under the curve (AUC) of 0.880, 0.921 and 0.905 for all (n=60), symptomatic (n=33) and asymptomatic patients (n=27) whereas classifiers using maximum accumulated strain indices alone provided AUC values of 0.817, 0.815 and 0.813 respectively.

The role played by vessel disease in stroke-related cognition dysfunction is unclear. We assessed the impact of significant atherosclerotic disease on cognition-even in patients asymptomatic for stroke. We hypothesized that patients would perform poorly relative to controls, but that symptomatic/asymptomatic status (history of stroke/transient ischemic attack) would have no effect. Fifty-two carotid endarterectomy candidates with >60% carotid stenosis and 17 controls underwent a 60-min neuropsychological test protocol. Symptomatic and asymptomatic patients showed deficits in executive function, delayed verbal recall, and general knowledge. Patients symptomatic for stroke also performed worse on tests of language and motor/visuomotor ability. Symptomatic and asymptomatic patients differed in working memory and language task performance. Although all patients showed deficits in executive function and memory, only symptomatic patients showed additional deficits in language and motor function. Cognitive abnormalities in patients viewed as "asymptomatic" for stroke underscore the need for early identification and treatment.

Grayscale median measurements are highly reproducible when obtained from the same US system with similar gain settings. Grayscale median values differ significantly across gain values and between systems. Researchers should consider the impact of US system and gain settings on GSM values when working to minimize system- and operator-dependent factors.

This study demonstrates the importance of vascular cognitive decline in atherosclerotic disease. This is a function of the degree of instability of the atherosclerotic plaque more than the presence of stroke symptoms. It further suggests that atherosclerotic vascular cognitive decline need not be inevitable, and may be modified by treating hypertension and removal of the unstable plaque. This highlights the need for continued research on the cognitive effects of cerebrovascular disease and the synergistic benefits of intensive medical and surgical therapy.