Regional Cerebral Glucose Metabolism Correlates with Bilateral Carotid Artery Calcification in Patients at-risk for Cardiovascular Disease and Healthy Volunteers

Introduction: Cardiovascular disease (CVD) is a leading cause of illness and death globally, primarily due to atherosclerosis. This disease reduces blood flow and oxygen delivery to organs, and when it affects the carotid arteries, can lead to cognitive impairment and dementia. Molecular imaging approaches can provide insight into the biological changes that contribute to brain dysfunction, such as CVD, before clinical symptoms occur. In the present study, we assessed the relationship between brain metabolism and CVD with positron emission tomography/computed tomography (PET/CT) imaging, selecting [¹⁸F] fluorodeoxyglucose (FDG) to measure cerebral glucose metabolism and [¹⁸F] sodium fluoride (NaF) to detect bilateral atherosclerotic calcification.

Methods: In total, 104 subjects (mean age 48.4 ± 14.1 years, 51% males) were selected from a total of 139 participants enrolled in the Cardiovascular Molecular Calcification Assessed by [¹⁸F] NaF PET/CT (CAMONA) study. This cohort included both patients at-risk for CVD and healthy volunteers (HVs) (n = 38 and n = 66, respectively) who underwent [¹⁸F] FDG and [¹⁸F] NaF PET/CT imaging. Quantification of [¹⁸F] FDG was performed with MIMneuro version 7.1.5. MIMneuro provides region-based analysis, with z-scores generated by comparing the patient to the selected age-matched set of normal controls. Bilateral carotid [¹⁸F] NaF uptake was quantified with OsiriX MD software v.13.0.1 by measuring the mean standardized uptake value (SUVmean) in the left and right common carotid arteries for each subject. A mixed-effects linear regression model was used to determine the relation between scaled [¹⁸F] FDG uptake and carotid artery calcification, correcting for carotid laterality as a within-subjects factor.

Results: [¹⁸F] FDG uptake in the brain inversely correlated with average bilateral carotid [¹⁸F] NaF uptake in specific regions, notably the cerebellum (b = -0.825, SE = 0.354, p = 0.021), cingulate gyrus (b = -1.232, SE = 0.540, p = 0.023), and medulla (b = -0.888, SE = 0.405, p = 0.029). In contrast, [¹⁸F] FDG uptake directly correlated with average bilateral carotid [¹⁸F] NaF uptake in the fusiform gyrus (b = 1.660, SE = 0.498, p = 0.001) and globus pallidus (b = 1.505, SE = 0.571, p = 0.009). Patient health status was found to have a significant interaction effect on the correlation between [¹⁸F] FDG and [¹⁸F] NaF uptake in the fusiform gyrus (b = -1.954, SE = 0.617, p = 0.001). Specifically, this correlation trended directly in at-risk patients but inversely in HVs.

Conclusions: Atherosclerotic plaque accumulation in the carotid arteries has potential implications for metabolic changes in brain regions governing cognition, emotion, sensory, and motor activities. Our findings support mounting evidence of the association between CVD and cognitive impairment, demonstrating regional hypometabolism in the presence of increased microcalcification of the carotid arteries. The observed direct correlations between [¹⁸F] FDG and [¹⁸F] NaF uptake in the fusiform gyrus and globus pallidus may point to potential compensatory mechanisms adopted by the brain in response to decreased blood perfusion. The vascular network of blood delivery to the brain is complex, with numerous arteries in addition to the carotid arteries supplying distinct brain regions. Future research efforts are needed to validate the clinical application of PET/CT in the detection of arterial calcification and risk of cognitive impairment.