Towards a mechanistic understanding of how age increases susceptibility to inflammation induced behavioural and cognitive disturbance

Periche Tomas, Eva 2023. Towards a mechanistic understanding of how age increases susceptibility to inflammation induced behavioural and cognitive disturbance. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Accumulating evidence implicates inflammation and the innate immune system in the pathophysiology of age-related cognitive decline and neurodegenerative disorders such as Alzheimer’s disease. However, we have a limited understanding of the mechanisms by which age may increase the susceptibility to the behavioural and cognitive impairments associated with inflammation. In this thesis, I developed and validated a new experimental model of mild acute inflammation (IFN-β injection) and integrated it with two different MRI methodologies, behavioural, cognitive, physiological and immunology data to investigate how age modulates the effects of inflammation on the brain. To achieve this, healthy young and old participants underwent two experimental sessions in which they each received IFN-β-1b (EXTAVIA® [100 μg]) and saline in randomised order. Two neuroimaging techniques were used to assess actions on the brain. 1) Resting-state functional magnetic resonance (rsfMRI) which was used to investigate functional connectivity architecture with a particular focus on the efficiency of information transfer. 2) Diffusion-Weighted Magnetic Resonance Spectroscopy (DW-MRS) which was used to explore whether this novel MRI-based method was sensitive to detecting changes in glial cells using a model of mild inflammation. Fatigue, sickness and mood questionnaires, as well as a battery of cognitive tasks (reward/punishment reinforcement learning task, psychomotor retardation and visuospatial memory tasks), were used to assess behavioural and cognitive changes. Physiological monitoring and serial blood draws were used to assess physiological and immunological responses. Key findings include demonstrating that: 1) IFN-β is a safe and robust new experimental model of mild acute inflammation, as shown by the changes observed in the physiological, immune and behavioural responses. 2) That DW-MRS is sufficiently sensitive to detect changes in glial morphometry induced by a model of mild inflammation (IFN-β). 3) That DW-MRS is sensitive to previously reported age-related differences in glial and neuronal densities and glial morphometry. 4) That IFN-β altered global brain functional connectivity architecture (rsfMRI data). Here, IFN-β particularly affected highly connected nodes (as has been reported in Alzheimer’s disease) and, the intensity of the effect varied with respect to age. Together, these data provide support for IFN-β as a model of mild acute inflammation and confirm the effectiveness of employing non-invasive imaging methods, in conjunction with a range of behavioural and cognitive tasks to investigate the impact of experimentally induced neuroinflammation in young and old individuals.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Psychology
Funders:	Hodge Foundation
Date of First Compliant Deposit:	5 March 2024
Last Modified:	05 Mar 2024 16:10
URI:	https://orca.cardiff.ac.uk/id/eprint/166888

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