Basal Cerebral Blood Flow Strongly Predicts Reductions to Cyclooxygenase Inhibition Across Brain Lobes in Healthy Humans

Background: Basal cerebral blood flow (CBF) varies 3-4-fold between individuals. While levels of hemoglobin and arterial CO 2 explain some of this variance, the key signaling mechanisms contributing to resting human CBF remain elusive. Cyclooxygenase (COX) inhibition with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) like indomethacin drastically but variably reduce CBF (20-45%). Interestingly, COX expression appears non-uniform across the human brain, and chronic NSAID use is associated with reduced risk of Alzheimer’s (AD) disease-a condition linked to altered CBF. We tested the hypothesis that healthy humans with higher basal CBF would exhibit larger COX-inhibited reduction in CBF. METHOD: 36 healthy young adults (18F) aged (24±8) participated in two magnetic resonance imaging (MRI) sessions using a double-blind, randomized, placebo-controlled design with the COX inhibitor, indomethacin (1.5 mg/kg). Female participants, not using hormonal birth control, were studied during days 1-7 of their menstrual cycle. All participants fasted > 8 hours and refrained from caffeine, NSAID use, and vigorous exercise for 24 hours prior to the scan. During each session, CBF was quantified using arterial spin labeling (ASL) MRI scans, enabling regional and lobular analysis of CBF in both grey matter (GM) and white matter (WM), as well as across subcortical regions, brainstem and cerebellum and the five major brain lobes including frontal, parietal, temporal and occipital lobes. Data were analyzed using regression models to examine the relationship between baseline CBF and the magnitude of blood flow reduction following indomethacin administration, with significance set at P < 0.05. Results are presented as mean ± standard deviation (SD). Results: Oral indomethacin decreased CBF in GM (47±14 to 24±7 mL/100g/min, p < 0.05) and WM (29±7 to 16±5 mL/100g/min, p < 0.05). Furthermore, a significant relationship was observed between baseline CBF and the extent of indomethacin-induced reductions, such that higher baseline CBF correlated with greater reductions in blood flow across all regions, explaining 62-87% of variation in basal CBF. The coefficients of determination (R 2 ) for these regressions were: GM (0.72), WM (0.65), brainstem and cerebellum (0.87), subcortical regions (0.62), frontal lobe (0.65), temporal lobe (0.65), parietal lobe (0.74), and occipital lobe (0.83) (p all < 0.05). Conclusion: Multiple strong positive correlations between basal CBF and the level of indomethacin induced reduction in CBF across all brain regions studied support the hypothesis. These data suggest that COX signaling plays a critical role in modulating basal CBF and may have important implications for understanding the mechanisms of vascular regulation and may contribute to our understanding of altered CBF in aging, stroke, and neurodegenerative diseases, particularly in relation to NSAID use. NIH R01 HL 150361 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.