An experimental and clinical investigation of the brain response in inflammatory arthritis

Herron, James W. (2023) An experimental and clinical investigation of the brain response in inflammatory arthritis. MD thesis, University of Glasgow.

Abstract

Rheumatoid arthritis (RA) and other inflammatory disorders are associated with a significant burden of mental disorder, including fatigue, cognitive problems, depression, and an enhanced risk of developing dementia in later life. The mechanisms underlying these associations are unclear, though inflammatory effects on the brain are thought to play an important role. Increasing evidence supports a role for communication of immune signals from the periphery to the brain, with structural and functional consequences. There is a lack of data from disease-relevant tissue-specific inflammatory animal models with translational potential.

This thesis sets out to explore the brain response to inflammatory arthritis using a translational approach, spanning measurement of the neuroinflammatory response in the collagen induced arthritis (CIA) mouse model, to the role of inflammatory variables in sickness behaviour in early RA, particularly fatigue, using a clinical cohort study.

CIA was found to be associated with a brain inflammatory response involving upregulated brain transcription of the pro-inflammatory cytokine interleukin-1- beta (Il1β) and the associated P2x7 receptor. An increased density of IBA1+ cells were demonstrated in the thalamus of arthritic mice, but not elsewhere in the brain. There was no indication of a consistent pattern of chemokine transcriptional changes, leukocyte recruitment to the brain or alterations in markers of plasticity such as hippocampal neurogenesis or neuronal density.

In the clinical cohort drawn from the Scottish Early Rheumatoid Arthritis (SERA) study, fatigue was examined in its relationship with variables relevant to the burden of peripheral inflammation at baseline, 6 and 12 months. While overall levels of fatigue improved markedly within the cohort over time, univariable and multivariable analysis did not reveal a consistent relationship between inflammatory or disease activity variables and fatigue. Fatigue was more closely related to pain, mood, anxiety and subjective patient reported outcome measures.

The experimental and clinical investigation presented in this thesis highlights the nuanced and complex relationship between peripheral inflammation and the brain response in the context of inflammatory arthritis. Further work is needed to broaden the field of knowledge using tractable and disease-faithful animal models and translational approaches. Further work in this area is vital to the endeavour to enhance our understanding and treatment of mental disorder in the context of inflammatory disease and may yield insights relevant to the role of inflammation in psychiatric disorders more broadly.

• Item Type: Thesis (MD)
• Qualification Level: Doctoral
• Subjects: Q Science > QR Microbiology > QR180 Immunology; R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Supervisor's Name: Cavanagh, Prof. Jonathan and Harnett, Prof. Maggie
• Date of Award: 2023
• Depositing User: Theses Team
• Unique ID: glathesis:2023-83475
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 08 Mar 2023 14:46
• Last Modified: 18 Jan 2024 08:30
• Thesis DOI: 10.5525/gla.thesis.83475
• URI: https://theses.gla.ac.uk/id/eprint/83475