SPECT/CT imaging reveals CNS-wide modulation of glymphatic cerebrospinal fluid flow by systemic hypertonic saline

Tuomas O Lilius, Marko Rosenholm, Laura Klinger, Kristian Nygaard Mortensen, Björn Sigurdsson, Frida Lind-Holm Mogensen, Natalie L Hauglund, Malthe Skytte Nordentoft Nielsen, Tomi Rantamäki, Maiken Nedergaard*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Intrathecal administration enables central nervous system delivery of drugs that do not bypass the blood-brain barrier. Systemic administration of hypertonic saline (HTS) enhances delivery of intrathecal therapeutics into the neuropil, but its effect on solute clearance from the brain remains unknown. Here, we developed a dynamic in vivo SPECT/CT imaging platform to study the effects of HTS on whole-body distribution of the radiolabeled tracer 99mTc-DTPA administered through intracisternal, intrastriatal, or intravenous route in anesthetized rats. Co-administration of systemic HTS increased intracranial exposure to intracisternal 99mTc-DTPA by ∼80% during imaging. In contrast, HTS had minimal effects on brain clearance of intrastriatal 99mTc-DTPA. In sum, SPECT/CT imaging presents a valuable approach to study glymphatic drug delivery. Using this methodology, we show that systemic HTS increases intracranial availability of CSF-administered tracer, but has marginal effects on brain clearance, thus substantiating a simple, yet effective strategy for enhancing intrathecal drug delivery to the brain.
Original languageEnglish
Article number105250
JournaliScience
Volume25
Issue number10
DOIs
Publication statusPublished - 21 Oct 2022

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