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-ß (Aß) antibody, obtaining a 5-fold increase in antibody binding to Aß plaques. Thus, manipulation of glymphatic activity may represent a novel strategy for improving penetration of therapeutic antibodies to the CNS.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid beta-Peptides/antagonists & inhibitors , Cerebrospinal Fluid/metabolism , Glymphatic System/metabolism , Immunotherapy/methods , Alzheimer Disease/pathology , Animals , Blood-Brain Barrier/metabolism , Disease Models, Animal , Fluorescent Dyes/administration & dosage , Fluorescent Dyes/pharmacokinetics , Glymphatic System/diagnostic imaging , Glymphatic System/drug effects , Humans , Immunologic Factors/administration & dosage , Immunologic Factors/pharmacokinetics , 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 & dosageABSTRACT
In advection-reaction-diffusion systems, the spreading of a reactive scalar can be significantly influenced by the flow field in which it grows. In systems with sharp boundaries between reacted and unreacted regions, motion of the reaction fronts that lie at those boundaries can quantify spreading. Here, we present an algorithm for measuring the velocity of reaction fronts in the presence of flow, expanding previous work on tracking reaction fronts without flow. The algorithm provides localized measurements of front speed and can distinguish its two components: one from chemical dynamics and another from the underlying flow. We validate that the algorithm returns the expected front velocity components in two simulations and then show that in complex experimental flows, the measured front velocity maps fronts from one time step to the next self-consistently. Finally, we observe a variation of the chemical speed with flow speed in a variety of experiments with different time scales and length scales.
ABSTRACT
We present an algorithm for measuring the speed and thickness of reaction fronts, and from those quantities, the diffusivity and the reaction rate of the active chemical species. This front-tracking algorithm provides local measurements suitable for statistics and requires only a sequence of concentration fields. Though our eventual goal is front tracking in advection-reaction-diffusion, here we demonstrate the algorithm in reaction-diffusion. We test the algorithm with validation data in which front speed and thickness are prescribed, as well as simulation results in which diffusivity and reaction rate are prescribed. In all tests, measurements closely match true values. We apply the algorithm to laboratory experiments using the Belousov-Zhabotinsky reaction, producing speed, diffusivity, and reaction rate measurements that are statistically more robust than in prior studies. Finally, we use thickness measurements to quantify the concentration profile of chemical waves in the reaction.
ABSTRACT
We experimentally study spreading of the Belousov-Zhabotinsky reaction behind a bluff body in a laminar flow. Locations of reacted regions (i.e., regions with high product concentration) correlate with a moderate range of Lagrangian stretching and that range is close to the range of optimal stretching previously observed in topologically different flows [T. D. Nevins and D. H. Kelley, Phys. Rev. Lett. 117, 164502 (2016)]. The previous work found optimal stretching in a closed, vortex dominated flow, but this article uses an open flow and only a small area of appreciable vorticity. We hypothesize that optimal stretching is common in advection-reaction-diffusion systems with an excitation threshold, including excitable and bistable systems, and that the optimal range depends on reaction chemistry and not on flow shape or characteristic speed. Our results may also give insight into plankton blooms behind islands in ocean currents.
ABSTRACT
We investigate growth of the excitable Belousov-Zhabotinsky reaction in chaotic, time-varying flows. In slow flows, reacted regions tend to lie near vortex edges, whereas fast flows restrict reacted regions to vortex cores. We show that reacted regions travel toward vortex centers faster as flow speed increases, but nonreactive scalars do not. For either slow or fast flows, reaction is promoted by the same optimal range of the local advective stretching, but stronger stretching causes reaction blowout and can hinder reaction from spreading. We hypothesize that optimal stretching and blowout occur in many advection-diffusion-reaction systems, perhaps creating ecological niches for phytoplankton in the ocean.
