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
Affiliations
Tuomas O. Lilius
Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Department of Emergency Medicine and Services, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
Marko Rosenholm
Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Laura Klinger
Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Kristian Nygaard Mortensen
Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Björn Sigurdsson
Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Frida Lind-Holm Mogensen
Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Neuro-immunology Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg; Doctoral School of Science and Technology, University of Luxembourg, Esch-sur-Alzette, Luxembourg
Natalie L. Hauglund
Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Malthe Skytte Nordentoft Nielsen
Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Tomi Rantamäki
Laboratory of Neurotherapeutics, Doctoral Program in Drug Research, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland; SleepWell Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Maiken Nedergaard
Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, 601 Elmwood Avenue, Box 645, Rochester, NY 14642, USA; Corresponding author
Summary: 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 single-photon emission computed tomography (SPECT)/computed tomography (CT) imaging platform to study the effects of HTS on whole-body distribution of the radiolabeled tracer 99mTc-diethylenetriaminepentaacetic acid (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 cerebrospinal fluid-administered tracer, but has marginal effects on brain clearance, thus substantiating a simple, yet effective strategy for enhancing intrathecal drug delivery to the brain.
