Role of Carotid Disease in Cognitive Impairment and Dementia

Carotid disease is a major cause of stroke and doubles the risk of cognitive impairment. People with cognitive impairment have trouble remembering, learning, concentrating, or making decisions that affect their everyday life. This condition has a significant socioeconomic impact on Veterans and their families. Carotid revascularization is commonly offered for patients with severe carotid narrowing for stroke prevention and is shown to be effective in appropriately selected patients. There are several types of carotid interventions. It is unclear when a particular type of intervention should be offered as the risks of stroke and death associated with carotid intervention are equally low across interventional types. However, up to 30% of patients experience procedure-related cognitive deterioration despite no neurologic complications. Identifying those patients at risk for procedure-related cognitive decline before the intervention can help to better select patients for appropriate intervention and reduce the future risk of dementia and cognitive impairment. Thus far, the mechanisms by which this cognitive decline occurs are poorly understood. Procedure-related silent brain infarcts (SBIs) due to microembolization are common (20-80%) and have been implicated in post-intervention cognitive decline. We observed that infarct size has a significant impact on their cognitive effects. Traditionally, SBIs and low blood flow are considered two independent etiologies that contribute to cognitive decline. There is a growing appreciation that they interact in the concept of the hemodynamic risk area. We recently observed an overlap between the areas of reduced cerebral blood flow and the brain areas vulnerable to procedure- related SBIs, suggesting an intimate relationship between perfusion and embolization. Based on the available evidence, we believe that blood flow reduction in the hemodynamic risk area contributes to the frequency, size, and cognitive effects of procedure-related SBIs. In this proposal, we will include novel MRI techniques to determine how cerebral blood flow impacts the characteristics and cognitive effect of SBIs. Increasing evidence supports the ability of the brain to mount an inflammatory response to a variety of injuries including ischemia and trauma. We also observed a significant correlation between inflammatory cytokines and intervention- related cognitive changes, suggesting that chemicals in blood react to injury, i.e. SBIs, and can help to predict cognitive changes following carotid interventions. Therefore, easily obtainable blood biomarkers can be used to identify a subgroup of patients at risk for post-procedure cognitive deterioration who benefit from early cognitive intervention. Early cognitive training in elderly adults with mild or early cognitive impairment has been shown effective in improving function. We plan a multi-site study to prospectively recruit 250 patients who undergo carotid intervention for severe asymptomatic carotid disease to decipher the interactions among brain perfusion, procedure-related infarcts, and plasma biomarkers. We will first compare the cognitive impact of different types of carotid interventions and determine the characteristics of infarcts, including size and location, that lead to cognitive dysfunction. Then, we plan to evaluate the impact of baseline brain perfusion on the frequency and size of infarcts as well as procedure-related cognitive changes. Lastly, we will examine the blood biomarkers that may predict cognitive decline following carotid interventions, focusing on the potential ones that we identified in our preliminary study. This proposal will clarify the controversy of cognitive effects of carotid intervention, and identify blood and imaging biomarkers that can be potentially used to predict at-risk Veterans for significant cognitive decline post- procedure. Identifying the subgroup of Veterans at risk before the revascularization procedure to individual Project Number: 1I01CX002260-01A2 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Wei Zhou | Institution: SOUTHERN ARIZONA VA HEALTH CARE SYSTEM, TUCSON, AZ | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 NURD-E (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11052703