Estimation of human brain fluid clearance using intrathecal imaging contrast agents

Area of Science:

• Neuroscience
• Radiology
• Pharmacokinetics

Background:

• Brain fluid dynamics, including glymphatic and meningeal lymphatic pathways, are crucial for central nervous system waste clearance.
• While animal studies suggest their importance, human data on inter-individual variability in brain fluid clearance is limited.
• This study aimed to assess the feasibility of estimating brain fluid clearance in humans using intrathecal imaging contrast agents.

Purpose of the Study:

• To investigate the feasibility of estimating human brain fluid clearance indices using intrathecal imaging contrast agents.
• To quantify inter-individual variability in brain fluid clearance and its distribution within the cerebrospinal fluid (CSF).
• To compare the efficacy of computed tomography (CT) and magnetic resonance imaging (MRI) in assessing brain fluid clearance.

Main Methods:

• A prospective observational study involving intrathecal administration of iodixanol (CT) and gadobutrol (MRI) as CSF tracers.
• Population pharmacokinetic modeling was used to quantify tracer clearance from CSF to blood.
• Intracranial tracer enrichment was assessed using CT radiodensity and MRI T1 signal increase in subarachnoid spaces at multiple time points.

Main Results:

• The study included 52 subjects for iodixanol and 45 for gadobutrol, revealing marked inter-individual variability in brain fluid clearance and CSF distribution for both agents.
• Brain fluid clearance of iodixanol and gadobutrol were significantly correlated.
• Gadobutrol-derived MRI metrics showed stronger correlations with intracranial distribution than iodixanol-derived CT metrics.

Conclusions:

• Intrathecal imaging contrast agents are feasible for estimating human brain fluid clearance.
• Brain fluid clearance capacity shows significant inter-individual variability and correlates with intracranial contrast enrichment, especially with MRI.
• Individualized assessment of brain fluid clearance is important for understanding neurodegenerative diseases and optimizing intrathecal drug delivery.