# A study of paravascular and interstitial flow in Hydrocephalus and shunting

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2021 · $204,688

## Abstract

PROJECT SUMMARY
In the last decade it has become clear that our understanding of hydrocephalus and the cerebrospinal fluid
(CSF) circulation is incomplete. New information, such as 1) the description of CSF secretion and absorption
within the brain, 2) the uncovering of oscillatory movements within the CSF, 3) the discovery of pathways that
lead from CSF spaces into the brain parenchyma through paravascular channels, and 4) new pathways out via
lymphatic drainage systems, has led to the understanding of a complex flow system which could ultimately
better explain hydrocephalus and lead to more physiological treatments. While anatomic details guiding this
flow of fluids and solutes are still unknown, their discovery would likely be a key to solving longstanding
problems in understanding parenchymal changes in hydrocephalus and in achieving a treatment that allows a
more physiological fluid regulation without over-and under-drainage. In this study we hypothesize a change in
pattern and direction of net fluid flow between brain and CSF spaces that results in hydrocephalus and
shunting failures. Anatomically this includes the reversal of fluid flow between the brain surface and ventricles.
The use of our large-animal model of obstructive hydrocephalus, along with MRI tracking of Gadobutrol (604
Da) and fluorescent imaging of molecular tracers (Alexa Fluor® 594 Hydrazide 758 Da, Dextran Lysine-fixable
3 kDa and 500 kDa) will allow the study of the activity of paravascular and interstitial flow in a controlled and
clinically relevant manner, including changes with hydrocephalus and after variable CSF shunting. Canines will
be distributed in three groups: normal control, obstructive hydrocephalus and shunted hydrocephalus. In Aim 1,
we will assess the paravascular, interstitial and trans-ependymal flow in healthy canines, to understand the
normal physiologic patterns of solute distribution around and inside the brain. In Aim 2, we will study the effects
of obstructive hydrocephalus on these pathways of flow, investigating the signature that this pathology leaves
on them, and their role in the onset of common symptoms and complications of hydrocephalus. In Aim 3, our
focus will shift to CSF shunting, and the consequences that this has on the interstitial, paravascular and trans-
ependymal systems. We hypothesize that interstitial flow reversals will be seen in hydrocephalus and shunting,
and that parenchymal changes in hydrocephalus will be associated with changes in fluid and solute influx into
brain from the ependyma and the paravascular pathways. This proposal, using multiple molecules and
modalities, will be the first to demonstrate changes in solute movement in the canine brain in hydrocephalus
and after treatment, opening a new avenue in understanding the physiopathology pathology of hydrocephalus
in a clinically relevant canine model. Moreover, this approach can be extended to a variety of contexts and
treatment issues, such as over- and undershunt...

## Key facts

- **NIH application ID:** 10142552
- **Project number:** 5R21NS116430-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Mark Gregory Luciano
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $204,688
- **Award type:** 5
- **Project period:** 2020-04-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10142552

## Citation

> US National Institutes of Health, RePORTER application 10142552, A study of paravascular and interstitial flow in Hydrocephalus and shunting (5R21NS116430-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10142552. Licensed CC0.

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