Assessment of CSF drainage to the lymphatic system using positron emission tomography in rats and nonhuman primates.

Objectives Understanding the biokinetics of drugs administered to the CSF benefits the development of effective treatments for diseases involving the CNS and meninges. Literature suggests that drug molecules are transferred from the CSF to the systemic circulation through: (1) micron-range pores in arachnoid granulations that drain directly to the blood, and (2) the lymphatic system. The extent, routes, and species-dependence of this lymphatic drainage are still widely debated. The goal of this study was to investigate the lymphatic uptake of solutes from the CSF using a minimally invasive, PET-based approach.

Methods Radiolabeled proteins and nanoparticles were administered into the CSF of rats and Cynomolgus monkeys through pre-implanted catheters opening in the lumbar segment of spine or in the brain ventricle. PET images were acquired over 24 hours. The imaging data was used to assess the extent of accumulation of the administered proteins and particles in the lymph nodes.

Results In animals with preinstalled catheters, the amount of the administered material that accumulated in the lymph nodes of both species was much lower than some previously reported data would suggest, especially in primates. Our data indicates only minor uptake in the lymph nodes, and almost exclusively in the cervical region. In rats, the total lymphatic uptake was 4.3±2.0%ID (n=9) and in primates, was 0.27±0.20%ID (n=9) four hours after the administration. (Notably, minor leakages from direct injection sites resulted in rapid material uptake in the respective sentinel lymph nodes.)

Conclusions Our findings suggest that CSF drainage directly to the blood is the main pathway by which the vast majority of macromolecules and particles exit the CSF into systemic circulation, especially in primates.