The Role of Large Artery Plaque Imaging Features in Predicting Inflammation and Cognition

Amyloid Deposition and Preexisting Vulnerable Carotid Plaque Features Predicting Cognitive Improvement After Surgery

The invesigators propose a clinical study on patients undergoing carotid surgery (endarterectomy). The invesigators will determine carotid artery imaging features associated with (1) vessel wall inflammation, (2) downstream brain inflammation, and (3) cognitive benefit from surgery. This project will uncover links between inflamed carotid plaque and downstream brain inflammation. The invesigators will also determine carotid plaque imaging features predicting cognitive benefit from carotid surgery.

This research is directed at a major stroke source, the carotid artery, a major vessel that supplies blood to the brain. It has long been known that carotid narrowing is an important stroke risk factor. However, many patients with narrow carotids do not have strokes, and many patients with seemingly normal carotids have strokes. MRI research now suggests that the carotid wall itself is the stroke source. Using carotid MRI, clinicians can identify previously invisible markers of unstable carotid plaque, including carotid wall bleeds (intraplaque hemorrhage). The working hypothesis is that patients with these unstable carotid plaques may have higher inflammation in both their carotid arteries and brain. This inflammation has been implicated in other diseases, including dementia. Carotid wall bleeds can easily be seen with carotid MRI, but are often invisible on ultrasound and CT scans. By using MRI, the invesigators have found that this silent killer is an important stroke risk factor even without carotid narrowing. Now that imaging can detect carotid wall bleeds, where do the bleeds come from? Recent research points to inflammation within the carotid wall. The invesigators plan to use histology to detect this inflammation in the vessel wall. Another question is, does inflammation in the carotid wall lead to inflammation in the brain? Using PET scans, the invesigators plan to determine whether inflammation in the brain is linked to carotid disease. Lastly, the invesigators hope to find out if carotid wall inflammation contributes to memory loss and if surgery is beneficial in these patients. The invesigators hope to detect this inflammation in the vessel wall and brain before patients develop stroke, memory loss and dementia. This will be of huge benefit not only in the detection of diseases, but would also allow clinicians to monitor treatment effect on both carotid disease and brain inflammation. The invesigators also hope to use these tools to detect early treatment response. This research will accelerate the pace of future clinical trials to bring important new medications to patients sooner.

This is a diagnostic-interventional cohort study in patients undergoing carotid endarterectomy for atherosclerotic disease.

All subjects will undergo diagnostic imaging as the intervention. This imaging will be with flutemetamol F 18 PET/CT

Carotid plaque inflammation will be calculated with quantitative immunohistochemistry and correlated with intraplaque hemorrhage while controlling for confounders.

Outcome 2. The primary outcome, brain inflammation will be compared in carotid intraplaque hemorrhage positive and negative sides, controlling for confounders including stenosis and perfusion.

Preoperative MRI-detected carotid intraplaque hemorrhage and prediction of cognitive improvement after endarterectomy.

Outcome 3. The primary outcome, difference in cognitive score will be compared in carotid intraplaque hemorrhage positive and negative patients, controlling for stenosis, perfusion and ischemic symptoms.

Inclusion Criteria: • Patients ≥18 years old and plans for carotid endarterectomy. Exclusion Criteria: Patients with carotid occlusion will be excluded, due to one carotid contributing to both right and left brain blood supply. Other known sources of cardioembolism, including atrial fibrillation, mechanical heart valve, left atrial or ventricular thrombus or intracardiac mass, endocarditis, EF <30% Known stroke mimics including multiple sclerosis or brain tumor MRI contraindications per ACR guidelines, including patients with pacemakers, renal failure with eGFR<30 ml/min/1.73m2, and contrast allergy [18F]Flutemetamol contraindications per manufacturer guidelines, including patients with prior reactions Known stage IV malignancy Pregnancy

All data will be made freely and publicly available on ClinicalTrials.gov within 12 months of the end of the funding period (and any no-cost extension). Carotid intraplaque hemorrhage Carotid plaque inflammation on histology Age, stroke status, male sex, smoking and vitamin D level Statin, antiplatelet, or antihypertensive use Ipsilateral brain inflammation measured by PET Carotid stenosis and perfusion parameters Cognitive score