- Title
- Investigating intracranial pressure elevation and the cerebrospinal fluid proteome post-stroke
- Creator
- Hood, Rebecca Joan
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2019
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Background: Our group have recently made a number of important findings regarding intracranial pressure (ICP) elevation post-stroke. Until recently, it was assumed that only patients with large, malignant infarction experienced ICP elevation. However, recent experimental and clinical findings from our laboratory suggest the existence of ICP elevation at 24 hours after mild-moderate stroke. The assumption was that this patient population did not experience ICP elevation due to small volumes of cerebral oedema (the assumed cause of ICP elevation in all disorders of neurological injury). When investigating the underlying mechanism behind the dramatic, yet transient ICP elevation after mild-moderate stroke in rats we discovered that the rise occurred independently of oedema, suggesting a novel mechanism of ICP elevation. Further investigation into the mechanisms led to the discovery that the 24 hour ICP rise can be triggered in stroke-free animals, by administration of cerebrospinal fluid (CSF) from stroke animals. Preliminary evidence, from studies transfusing human stroke-CSF into rats, suggests that the ICP trigger may also exist in human CSF. Stroke is known to alter CSF composition and there have been a handful of studies showing correlation between CSF proteins e.g. arginine vasopressin (AVP) and ICP elevation. Aims: The aims of this PhD were to 1) Confirm the accuracy and reliability of epidural pressure measurement in rats using a fibreoptic pressure sensor. 2) Determine whether intraventricular infusion of AVP causes delayed ICP elevation in naïve rats. 3) Determine whether intraventricular infusion of human stroke-CSF causes ICP elevation in naïve rats. 4) Identify potential protein candidates in human stroke-CSF that may be responsible for delayed ICP elevation. Methods: Accuracy and reliability of epidural pressure measurement was assessed over a range of pressures against both subdural and intraventricular pressure (the gold standard). Epidural pressure measurement was then used to monitor changes in ICP following infusion of AVP (0.02–5 ng) or human CSF (from patients diagnosed with stroke, chronic hydrocephalus, subarachnoid haemorrhage, or control patients) into naïve (disease free) outbred, Wistar rats. Human CSF samples were then analysed using a Q-Exactive Plus mass spectrometer to determine relative protein expression. Stroke- and chronic hydrocephalus-CSF samples that caused ICP elevation ≥5 mmHg in the recipient animals were compared against samples that did not cause a rise in ICP. Results: Epidural pressure measurement was shown to demonstrate a strong correlation across a range of pressures, with pressure measured in both the subdural (ρc = 0.89) and intra-ventricular spaces (ρc = 0.11). Preliminary experiments found that infusion of AVP did not cause significant ICP elevation above baseline (n = 4/ group; p>.05). Infusion of both stroke- and chronic hydrocephalus-CSF caused significant delayed ICP elevation in recipient animals (p=.02 and .002 respectively). Investigation of the stroke and hydrocephalus CSF proteomes resulted in the identification of 17 and 32 proteins respectively showing significantly altered expression when ICP elevating samples were compared against samples that did not affect ICP. Galectin -1 and Calcium/calmodulin dependent protein kinase II beta were identified as being significantly more abundant in the samples that caused ICP elevation in both stroke- and chronic hydrocephalus-CSF samples. Conclusions: In this thesis, I have presented data that expands upon the working hypothesis that CSF composition is important in the delayed ICP elevation seen in humans and animals 24 hours after mild-moderate stroke. My findings confirm the validity of epidural pressure measurement in rats and expand on previous findings by showing this using fibreoptic pressure sensing technology. Secondly, my data indicates that AVP is unlikely to be the primary driver behind the delayed ICP elevation seen at 24 hours post-stroke in rats. Thirdly, my data suggests the presence of a molecular trigger for ICP elevation in the CSF of human stroke patients. Furthermore, by showing a similar rise in ICP following infusion of human stroke-CSF I have confirmed the clinical relevance of our animal work. Finally, I have identified two candidates of interest that may be important for ICP regulation not just post-stroke but also for patients with chronic hydrocephalus. These proteins may be potentially important for the diagnosis of stroke patients at risk of developing damaging ICP elevation. They may also be relevant to other neurological conditions involving ICP elevation. These preliminary findings are strongly suggestive of a novel mechanism of ICP elevation after stroke and justify further investigation into other neurological diseases of which ICP elevation is a harmful consequence.
- Subject
- ischaemic stroke; cerebrospinal fluid; intracranial pressure
- Identifier
- http://hdl.handle.net/1959.13/1411994
- Identifier
- uon:36413
- Rights
- Copyright 2019 Rebecca Joan Hood
- Language
- eng
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 7 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 158 KB | Adobe Acrobat PDF | View Details Download |