Stroke is the most common cause of permanent disability, and remains the third leading cause of death in industrialized countries. Carotid endarterectomy (CEA) and stenting (CAS) have shown to be effective in stroke prevention. However, only clinically evident embolization has been evaluated as an outcome measure;subclinical microemboli have not been fully assessed. Several studies have confirmed that microemboli demonstrated on diffusion-weighted MRI (DWI) during CAS are common despite absence of clinical symptoms. To date, the clinical significance of microemboli and their long-term effects on cognitive function are largely unknown. To elucidate these important issues, we propose an intense longitudinal investigation using a multidisciplinary team approach at two academic centers. Our central hypothesis is that subclinical microembolization moderates the degree of cognitive changes following CAS and that development of microemboli themselves is associated with patients- and procedure- related factors.
Three specific aims are proposed to address this urgent issue:
Specific Aim 1 : Determine the clinical significance of the development of DWI abnormalities for short- and long-term changes in cognitive function in patients with subclinical microemboli;
Specific Aim 2 : Evaluate patient risk factors for subclinical microembolization following CAS;
and Specific Aim 3 : Identify technical factors contributing to procedure-related subclinical microemboli during CAS. The investigators and collaborators have complementary expertise and a track record of clinical research in the areas of carotid disease (WZ, RLD, MGD), brain imaging (BL, AR, ZG), and cognitive function (AR, JY, LL). Statistical analyses will be conducted in consultation with Dr. Lazzeroni, an experienced biostatistician. Through this proposal and collaborative efforts of multidisciplinary team experts, we hope to understand three key questions: Are subclinical microemboli clinically relevant? Do they affect long-term neurocognitive function? What are the risk factors for microemboli? Understanding these fundamental issues is essential to optimizing our strategy in stroke prevention through proper patient selection, a better treatment approach, and possible refinement in interventional techniques. Reduction of potentially microemboli-associated cognitive impairment will also have a significant impact on future public health by decreasing vascular-related dementia. Ongoing debates regarding the treatment guideline for CAS raise the urgency of this study. The proposal may change our current clinical practice guideline by providing a better outcome measure for carotid interventions. Regardless of the cognitive effects of microemboli, risk factor stratification represents a unique opportunity for quality improvement in carotid interventions.

Public Health Relevance

Subclinical microemboli are common during carotid artery stenting (CAS) procedures for patients with high-grade stenoses despite absence of neurologic symptoms. Our goal is to evaluate long-term cognitive effects of, and risk factors for, microemboli through a multidisciplinary longitudinal approach, and our long-term goal is to optimize strategies in stroke prevention and to improve future public health by reducing embolization-related cognitive impairment. The proposal may change our current clinical practice by providing a better outcome measure for carotid interventions.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
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Moy, Claudia S
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Palo Alto Veterans Institute for Research
Palo Alto
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Zuniga, Mary C; Raghuraman, Gayatri; Zhou, Wei (2018) Physiologic levels of resistin induce a shift from proliferation to apoptosis in macrophage and VSMC co-culture. Surgery 163:906-911
Zuniga, Mary C; Raghuraman, Gayatri; Hitchner, Elizabeth et al. (2017) PKC-epsilon and TLR4 synergistically regulate resistin-mediated inflammation in human macrophages. Atherosclerosis 259:51-59
Zhou, Wei; Baughman, Brittanie D; Soman, Salil et al. (2017) Volume of subclinical embolic infarct correlates to long-term cognitive changes after carotid revascularization. J Vasc Surg 65:686-694
Zuniga, Mary C; Tran, Thuy B; Baughman, Brittanie D et al. (2016) A Prospective Evaluation of Systemic Biomarkers and Cognitive Function Associated with Carotid Revascularization. Ann Surg 264:659-65
Raghuraman, Gayatri; Zuniga, Mary C; Yuan, Hai et al. (2016) PKC? mediates resistin-induced NADPH oxidase activation and inflammation leading to smooth muscle cell dysfunction and intimal hyperplasia. Atherosclerosis 253:29-37
Soman, Salil; Prasad, Gautam; Hitchner, Elizabeth et al. (2016) Brain structural connectivity distinguishes patients at risk for cognitive decline after carotid interventions. Hum Brain Mapp 37:2185-94
Hitchner, Elizabeth; Baughman, Brittanie D; Soman, Salil et al. (2016) Microembolization is associated with transient cognitive decline in patients undergoing carotid interventions. J Vasc Surg 64:1719-1725
Hitchner, Elizabeth; Morrison, Doug; Liao, Phoebe et al. (2016) Genetic Polymorphisms Influence Cognition in Patients Undergoing Carotid Interventions. Int J Angiol 25:168-73
Hitchner, Elizabeth; Zhou, Wei (2015) Utilization of Intravascular Ultrasound during Carotid Artery Stenting. Int J Angiol 24:185-8
Zeng, Hongwu; Ramos, Camille Garcia; Nair, Veena A et al. (2015) Regional homogeneity (ReHo) changes in new onset versus chronic benign epilepsy of childhood with centrotemporal spikes (BECTS): A resting state fMRI study. Epilepsy Res 116:79-85

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