Ronald M. Lazar, Ph.D., professor and director of the Division of Neuropsychology in the UAB Department of Neurology A major clinical trial led by researchers at the University of Alabama at Birmingham has answered a long-standing question about the relationship between carotid artery disease and cognition: While patients with severe narrowing, or stenosis, of the carotid arteries often experience subtle cognitive deficits, restoring blood flow through surgical or minimally invasive procedures does not improve cognitive performance.
The findings, “Revascularization of Asymptomatic Carotid Artery Stenosis: Cognitive Results of the CREST-2 Randomized Trials,” published this month in JAMA, come from the cognitive study embedded in the landmark CREST-2 trial and represent the largest randomized investigation to date examining whether carotid revascularization can improve thinking and memory in patients with asymptomatic carotid artery stenosis. The study was led by Ronald M. Lazar, Ph.D., professor and director of the Division of Neuropsychology in the UAB Department of Neurology.
The research builds on previous work by Lazar and colleagues that found patients with severe asymptomatic carotid artery stenosis performed below expectations on cognitive testing despite having no history of stroke or other neurological symptoms. This work and that of others have shown that reduced blood flow to the brain is likely responsible for these cognitive changes. It is already known, says Lazar, that restoring blood flow when someone has severe stroke in the acute setting can restore much of the impaired function.
“All of these previous findings raised an important question: Can the cognitive deficits caused by reduced blood flow to the brain from a chronic blockage in the carotid artery be reversed by restoring circulation?” Lazar said.
The study was designed to answer that question. Investigators analyzed cognitive outcomes among more than 2,100 participants with asymptomatic carotid artery stenosis enrolled in the national CREST-2 trial. Participants were randomized to receive either intensive medical management alone or intensive medical management combined with carotid revascularization through carotid endarterectomy or carotid artery stenting.
“If restoring blood flow with revascularization improved cognition in otherwise asymptomatic patients, then there would be another reason to undergo a procedure to remove the blockage,” Lazar said.
Researchers followed participants for up to four years and assessed performance across multiple cognitive domains, including memory, attention, executive function and processing speed.
Despite successfully restoring blood flow in treated patients, the study found no significant cognitive advantage for either carotid endarterectomy or carotid artery stenting compared with intensive medical management alone.
The findings provide some of the strongest evidence to date that impaired blood flow alone may not fully explain the cognitive differences observed in patients with asymptomatic carotid artery disease.
Instead, the results suggest that the relationship between carotid artery disease and cognition is likely more complex and may involve broader vascular changes affecting the brain.
Currently, carotid endarterectomy and carotid artery stenting remain established treatments for select patients because of their potential role in reducing stroke risk. However, the new findings have important implications on patient care and indicate that cognitive improvement should not be considered an expected benefit of those procedures in patients beyond the stroke prevention.
“The data provides further support that prevention of cerebrovascular disease through risk factor management and lifestyle modifications, especially smoking cessation, reducing high blood pressure, a healthy diet and routine exercise, remain the best means to avoid carotid stenosis,” Lazar said.
Researchers say future studies will focus on uncovering the biological mechanisms linking carotid artery disease and cognition, including the potential roles of chronic vascular injury, microvascular disease and other factors affecting brain health.
Along with Lazar, co-authors include investigators from UAB, including Lloyd Edwards, Ph.D., School of Public Health; George Howard, Dr.PH., School of Public Health; Emma Storm, Marnix E. Heersink School of Medicine; Virginia Howard, Ph.D., School of Public Health; and Virginia G. Wadley, Ph.D., Department of Medicine. Additional authors represent Mayo Clinic Florida, University of Maryland School of Medicine, Novant Health, Yale School of Medicine, Medical University of South Carolina and Columbia University Irving Medical Center.
CREST-2 is a multicenter randomized clinical trial conducted at institutions across the United States and funded by the National Institutes of Health. In addition to the NIH, the CREST-2 trials were supported by the Centers for Medicare and Medicaid Services, StrokeNet, and additional support from Regeneron Pharmaceuticals.