Importance of CSF circulation following ischaemic stroke: A novel MRI investigation of CSF parenchymal flow

Alshuhri, Mohammed Shenan (2021) Importance of CSF circulation following ischaemic stroke: A novel MRI investigation of CSF parenchymal flow. PhD thesis, University of Glasgow.

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It has been proposed that intracranial pressure (ICP) elevation and collateral
failure are responsible for unexplained early neurological deterioration (END) in
stroke. Our aim was to investigate whether cerebrospinal fluid (CSF) dynamics,
rather than oedema, are responsible for elevation of ICP after ischaemic stroke.
Permanent middle cerebral artery occlusion (pMCAO) was induced with an
intraluminal filament. At 24 hours after stroke, baseline ICP was measured, and
CSF dynamics were probed via a steady-state infusion method. For the first
time, we found a significant correlation between the baseline ICP at 24 hours
post-stroke and the value of CSF outflow resistance. Results show that CSF
outflow resistance, rather than oedema, was the mechanism responsible for ICP
elevation following ischaemic stroke. This challenges current concepts and
suggests the possibility that intracranial hypertension may be occurring
undetected in a much wider range of stroke patients than is currently considered
to be the case.

Over the last decade, there has been significant renewed interest in the
anatomical pathways and physiological mechanisms for the circulation of CSF.
The glymphatic system is one such pathway that has been recently
characterised. This network drives CSF into the brain along periarterial spaces
and interstitial fluid (ISF) out along perivenous spaces. Aquaporin-4 (AQP4) water
channels, densely expressed at the vascular endfeet of astrocytes, facilitate
glymphatic transport. Glymphatic failure has been linked to a broad range of
neurodegenerative diseases including ischaemic stroke. Accordingly, if the
glymphatic circulation is a major outflow route for CSF, glymphatic dysfunction
following ischaemic stroke could alter CSF dynamics and, therefore, ICP.

Nevertheless, the glymphatic hypothesis is still controversial. All in vivo and
biomechanical modelling studies that have investigated the glymphatic system
have been based on utilizing a solute tracer to track the movement of CSF within
the intracranial space. Since 99% of CSF is water, it is questionable whether
nonwater tracer molecules can ever show the real dynamic flow of CSF.
Hence, we sought the develop of a new MRI method to directly image CSF
dynamics in-vivo, by exploiting an isotopically enriched MRI tracer, namely,
H217O. Our results reveal glymphatic flow that is dramatically faster and more
extensive than previously thought. Moreover, we confirm the critical role of
aquaporin-4 (AQP4) channels in glymphatic flow by imaging CSF water dynamics
in the brain using H217O alongside a potent blocker of AQP4. We hope in future
that this new method can be used to investigate the responsible mechanism for
the increased CSF resistance and ICP elevation following ischaemic stroke.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Subjects: Q Science > QP Physiology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Supervisor's Name: Holmes, Dr. William
Date of Award: 2021
Depositing User: Theses Team
Unique ID: glathesis:2021-82303
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 02 Jul 2021 14:18
Last Modified: 02 Jul 2021 14:18
Thesis DOI: 10.5525/gla.thesis.82303
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