Modeling of brain efflux: Constraints of brain surfaces

• 成果类型: Article
• 署名作者: Bork, Peter A. R.; Hauglund, Natalie L.; Mori, Yuki; Mollgard, Kjeld; Hjorth, Poul G.; Nedergaard, Maiken
• 署名单位: University of Copenhagen; University of Copenhagen; Technical University of Denmark
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15175
• DOI: 10.1073/pnas.2318444121
• 发表日期: 2024-04-16
• 关键词: blood-volume; transport; SPACE; diffusion; clearance; albumin; plasma

摘要

Fluid efflux from the brain plays an important role in solute waste clearance. Current experimental approaches provide little spatial information, and data collection is limited due to short duration or low frequency of sampling. One approach shows tracer efflux to be independent of molecular size, indicating bulk flow, yet also decelerating like simple membrane diffusion. In an apparent contradiction to this report, other studies point to tracer efflux acceleration. We here develop a one-dimensional advection- diffusion model to gain insight into brain efflux principles. The model is characterized by nine physiological constants and three efflux parameters for which we quantify prior uncertainty. Using Bayes' rule and the two efflux studies, we validate the model and calculate data -informed parameter distributions. The apparent contradictions in the efflux studies are resolved by brain surface boundaries being bottlenecks for efflux. To critically test the model, a custom MRI efflux assay measuring solute dispersion in tissue and release to cerebrospinal fluid was employed. The model passed the test with tissue bulk flow velocities in the range 60 to 190 gm/h. Dimensional analysis identified three principal determinants of efflux, highlighting brain surfaces as a restricting factor for metabolite solute clearance.