Quantifying Ventricular CSF Clearance in the Human Brain Using Dynamic 18F-FDG PET: Insights into Age-Related Glymphatic Impairment

Abstract

Purpose: The glymphatic system facilitates brain waste clearance via cerebrospinal fluid (CSF) flow, and its dysfunction has been linked to aging and neurodegeneration. However, clinically accessible methods to quantify glymphatic function in humans remain limited. This study aimed to examine the potential of dynamic 18F-FDG PET for measuring ventricular CSF clearance - as a surrogate marker of glymphatic function. Specifically, we evaluated its association with age, its test–retest reliability, and the feasibility of reduced scan durations for clinical applicability. Methods: We analyzed 72 baseline 18F-FDG PET scans from participants enrolled in a prior depression trial. Time–activity curves (TACs) were extracted from the lateral ventricles and fitted with a γ-variate model to estimate influx (𝜇𝑖𝑛) and clearance (𝜇𝑜𝑢𝑡) parameters. Associations with age and clinical factors were examined using correlation and multiple linear regression. Test–retest reliability was assessed in 11 placebo-treated participants who underwent repeat scans eight weeks apart. A feasibility analysis tested whether shorter scan windows could yield comparable clearance estimates. Results: 𝜇𝑜𝑢𝑡 showed a strong negative correlation with age (r = −0.680, p < 0.001), while 𝜇𝑖𝑛 was not significantly age-related. Age remained a significant predictor of 𝜇𝑜𝑢𝑡 after adjusting for sex, ventricle size, and depression severity. A positive association between 𝜇𝑜𝑢𝑡 and depression severity was observed after covariate adjustment. Test–retest analysis yielded an intraclass correlation coefficient of 0.702 for 𝜇𝑜𝑢𝑡, indicating moderate-to-good reproducibility. A shortened 30-minute scan window (starting 30 minutes post injection) preserved strong correlations with both 𝜇𝑜𝑢𝑡 and age, supporting the potential for abbreviated imaging protocols. Conclusion: Dynamic 18F-FDG PET provides a reliable and noninvasive method to quantify ventricular CSF clearance, revealing age-related decline indicative of glymphatic impairment. The method demonstrates reproducibility over time and retains key clearance metrics even with shortened scan durations. These findings establish a clinically feasible 18F-FDG PET-based approach for studying brain clearance and glymphatic function in aging and disease.