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

JCI Insight. 2018 Oct 18;3(20):e120922. doi: 10.1172/jci.insight.120922.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Animals
  • Blood-Brain Barrier / metabolism
  • Cerebrospinal Fluid / metabolism*
  • Disease Models, Animal
  • Fluorescent Dyes / administration & dosage
  • Fluorescent Dyes / pharmacokinetics
  • Glymphatic System / diagnostic imaging
  • Glymphatic System / drug effects
  • Glymphatic System / metabolism*
  • Humans
  • Immunologic Factors / administration & dosage
  • Immunologic Factors / pharmacokinetics
  • Immunotherapy / methods*
  • Injections, Intraventricular
  • Intravital Microscopy
  • Male
  • Mannitol / administration & dosage
  • Mice
  • Optical Imaging
  • Osmolar Concentration
  • Permeability / drug effects
  • Plasma / chemistry
  • Plasma / drug effects
  • Saline Solution, Hypertonic / administration & dosage


  • Amyloid beta-Peptides
  • Fluorescent Dyes
  • Immunologic Factors
  • Saline Solution, Hypertonic
  • Mannitol