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JCI Insight. 2018 Oct 18;3(20). pii: 120922. doi: 10.1172/jci.insight.120922.

Transcranial optical imaging reveals a pathway for optimizing the delivery of immunotherapeutics to the brain.

Author information

1
Center for Translational Neuromedicine, Department of Neurosurgery.
2
Department of Pathology, and.
3
Department of Neuroscience, University of Rochester Medical Center, Rochester, New York, USA.
4
Department of Mechanical Engineering and.
5
Department of Physics and Astronomy, University of Rochester, Rochester, New York, USA.
6
Laboratory of Metabolic Brain Diseases, Institute of Metabolic Disease Research and Drug Development, China Medical University, Shenyang, China.

Abstract

Despite the initial promise of immunotherapy for CNS disease, multiple recent clinical trials have failed. This may be due in part to characteristically low penetration of antibodies to cerebrospinal fluid (CSF) and brain parenchyma, resulting in poor target engagement. We here utilized transcranial macroscopic imaging to noninvasively evaluate in vivo delivery pathways of CSF fluorescent tracers. Tracers in CSF proved to be distributed through a brain-wide network of periarterial spaces, previously denoted as the glymphatic system. CSF tracer entry was enhanced approximately 3-fold by increasing plasma osmolality without disruption of the blood-brain barrier. Further, plasma hyperosmolality overrode the inhibition of glymphatic transport that characterizes the awake state and reversed glymphatic suppression in a mouse model of Alzheimer's disease. Plasma hyperosmolality enhanced the delivery of an amyloid-β (Aβ) antibody, obtaining a 5-fold increase in antibody binding to Aβ plaques. Thus, manipulation of glymphatic activity may represent a novel strategy for improving penetration of therapeutic antibodies to the CNS.

KEYWORDS:

Alzheimer’s disease; Immunotherapy; Neuroimaging; Neuroscience; Therapeutics

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