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Modelling aspects of Alzheimer’s disease pathology without the transgenics; understanding the effects of brain disease on neurovascular coupling and neuroimaging signals.

Brezzo, Gaia (2017) Modelling aspects of Alzheimer’s disease pathology without the transgenics; understanding the effects of brain disease on neurovascular coupling and neuroimaging signals. PhD thesis, University of Sheffield.

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G.Brezzo PhD THESIS.pdf
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Abstract

The aim of this research was to develop non-transgenic rodent models relevant to Alzheimer’s disease (AD) to investigate the effects of cholinergic, inflammatory and ageing manipulations upon neurovascular function and neurovascular coupling. The use of imaging techniques including functional magnetic resonance imaging (fMRI) have revolutionised the way in which we approach the study of the healthy human brain, helping to shed light onto the processes by which neurodegenerative diseases occur. Non-invasive imaging methods including fMRI are currently limited by their inability to measure neuronal activity directly. Thereby animal models are an invaluable tool in extending our understanding of the underling neurovascular coupling mechanisms, the connection between neuronal activity and blood flow, and their relationship to diseased states. In vivo neurovascular research is warranted as ample findings implicate altered biological mechanisms including neurovascular coupling in the pathogenesis of AD. In this thesis neurovascular function and coupling were investigated in vivo utilising a multi-modal approach by obtaining measures of haemodynamics and neuronal activity (with laser-speckle-contrast-imaging, two-dimensional optical imaging and multichannel electrodes) and by further informing upon these changes with immunohistochemistry. The major findings of this work are: (1) reduced cholinergic function leads to neurovascular uncoupling; (2) acute systemic inflammation alters in vivo haemodynamic function and; (3) is associated with significant underlying changes in the status of the neurovascular unit; and (4) in an early-ageing model inflammation-driven changes in haemodynamic function occur more rapidly after an acute challenge. These findings provide important insights into how disease-related mechanisms impact upon neurovascular coupling which in turn may directly impact upon the brain imaging signals acquired from clinical populations. Additionally, this thesis demonstrates that neurovascular coupling should be assessed across a range of stimulation input parameters in order to confidently determine the effects of experimental manipulations.

Item Type: Thesis (PhD)
Academic Units: The University of Sheffield > Faculty of Science (Sheffield) > Psychology (Sheffield)
Depositing User: Dr Gaia Brezzo
Date Deposited: 18 Dec 2017 09:23
Last Modified: 18 Dec 2017 09:23
URI: http://etheses.whiterose.ac.uk/id/eprint/18969

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