Kinetic analysis of CSF to brain tracer exchange in the pig brain under different anesthetic regimes

Authors

L. Navarro, M., Olsen, A. S., Ulv Larsen, S. M., Madsen, C., de Nijs, R., Pernet, C., Bubulovic, K., Sondergaard, J., Jorgensen, L. M., Svarer, C., Knudsen, G. M.

Abstract

Introduction: Anesthesia is known to modulate glymphatic clearance and cerebrospinal fluid (CSF) transport in rodents, but how these effects translate to a larger, gyrencephalic brain is unknown. With its anatomical similarity to the human brain, the pig offers a valuable translational model for examining anesthesia-dependent CSF-to-brain transport. Methods: We used dynamic in vivo SPECT/CT imaging for six hours following cisterna magna injection of [99mTc]-DTPA to quantify CSF-to-brain tracer transport in pigs under two anesthesia regimens: ketamine/dexmedetomidine (K/D, n=5) which previously has been shown in rodents to enhance glymphatic influx relative to GABAergic anesthesia, and propofol (PRO, n=5). Brain and CSF spaces were delineated using a data-driven non-negative matrix factorization approach, and tracer kinetics were quantified using a one-tissue compartment model. Results: Brain influx could be stably estimated from 2 hours post-injection. Hierarchical sub-division of the brain parenchyma identified two kinetically distinct components with different anatomical distributions: a surface component, located ventrally and within the interhemispheric fissure, showed faster kinetics than the anatomically deeper and lateral-dorsal component. Consistent with rodent findings, K/D-anesthetized pigs showed 62% (p=0.002) greater brain tracer accumulation than PRO-anesthetized pigs. However, while the brain influx rates did not differ substantially (p=0.047), a 52% higher cumulative CSF tracer concentration (p=0.047) could account for most of the difference by providing greater tracer availability for brain entry. Conclusions: In the larger gyrencephalic pig brain, we found higher brain tracer accumulation under K/D anesthesia compared to PRO anesthesia. A significant portion of this difference is readily explained by higher CSF retention, likely driven by a slower CSF turnover. This underscores the necessity of dynamic CSF tracer concentration measurements when assessing CSF-brain influx, a factor we suggest that future glymphatic studies should take into account.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 28 Aug 2026.

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