The neuroinflammatory basis of disease progression and cognitive impairment in Parkinson's disease

Parkinson’s disease (PD) is classically defined as a movement disorder, but a large proportion of patients also develop cognitive dysfunction as the disease progresses. Currently, it is not fully understood why some patients experience mainly movement-related features, whilst others suffer from a more aggressive disease course with the development of an early dementia. This latter complication is a key milestone in the progression of the disease; almost half of PD patients will develop dementia within 10 years of diagnosis, which has a profound impact on quality of life and care requirements. Abnormal protein aggregation in the form of cortical Lewy bodies and Alzheimer’s-type pathology are well-described pathological correlates of PD dementia, but what determines the rate of progression of this pathology and the time to dementia is unknown. A strong candidate which may play a key role to the rate of cognitive decline is neuroinflammation. Whilst immune activation is well-described in PD, how it links to protein aggregation and its role in PD dementia and disease progression has not been explored, and this forms the focus of this PhD thesis. I hypothesize that neuroinflammatory changes are a critical and early contributor to the pathology of PD dementia. Chapter 1 describes the background and rationale of this PhD thesis including a literature review of the neuropathology of Parkinson’s and its associated dementia. It also provides an overview of the role of the immune system in PD, with a particular focus on Toll-like receptors which are key molecules involved in the activation of the innate immune response. Chapter 2 describes a detailed neuropathological investigation of the distribution and characteristics of inflammatory change in postmortem PD and control brains. It also explores the correlation between neuroinflammatory change, aberrant forms of α-synuclein, tau and amyloid-β and the rate of cognitive decline during life. This study found an increase in activated microglia in the amygdala and hippocampus of PD brains compared to controls, accompanied by infiltration of T lymphocytes in the brain parenchyma. Increased expression of pro-inflammatory cytokines was also observed, both in the substantia nigra and amygdala, as well as upregulation in Toll-like receptors 2 (TLR2) and 4 (TLR4). Chapter 3 describes a study investigating the relationship between neuroinflammation, tau pathology and disease prognosis, in vivo, using PET neuroimaging in early PD. Patients were stratified according to their risk of rapid progression to dementia in “high” versus “low” risk groups, defined using novel clinical and genetic predictors. This study involved PET neuroimaging with [11C]PK11195, a marker of neuroinflammation, and [18F]AV-1451, a radioligand used to visualize tau accumulation, as well as immunophenotyping and TLR expression analysis in the blood and cerebrospinal fluid. PET imaging with [11C]PK11195 showed an increase in neuroinflammation in both PD groups compared to controls in the temporal and orbitofrontal cortex. Whilst [18F]AV-1451 binding was minimal in healthy individuals, it is markedly increased in both low and high risk PD patients in several brain regions. This study also found changes in lymphocyte and monocyte populations in the blood of PD patients compared to controls, as well as increased expression of TLR2 in monocytes, both in the blood and CSF. Chapter 4 describes a pilot study evaluating the time-course of neuroinflammatory change and Toll-like receptor expression in a novel rat model of α-synuclein. This in vivo model was based on the transvascular delivery of α-synuclein pre-formed fibrils. A secondary aim of this pilot study was to assess the tolerability of two TLR-blocking agents (Candesartan cilexetil and TAK242) and their efficacy in reducing TLR expression and protein levels over a two-month treatment in this model. This chapter showed a gradual increase in microglia in the brainstem, accompanied by an increase in TLR levels, particularly TLR4, at 2- 4- and 6-months post-α-synuclein injection. Both TLR-blocking agents were well-tolerated, but I could not demonstrate significant TLR blockade in this small pilot study. Chapter 5 presents the key conclusions of this PhD thesis. My postmortem work suggests that microglial activation is increased in brain areas associated with cognition, namely the hippocampus and the amygdala, and this is accompanied by increased expression of pro-inflammatory mediators. I also identified TLR2 and TLR4 as particular molecules of interest in postmortem PD brain, in biofluids of PD patients at early stages of the disease, and in a novel α-synuclein rodent model. Furthermore, I present in vivo imaging evidence of increased tau deposition in the brain in early PD. The end of the chapter discusses plans for further development of this work.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2019

Author dc:creator

• Kouli, Antonina

Advisors dc:contributor.advisor

• Barker, Roger Alistair
• Williams-Gray, Caroline Helen

• Parkinson's disease
• Neuroinflammation
• Dementia
• PET neuroimaging
• Microglia

Statement dc:rights

• This thesis includes modified excerpts of an open access book chapter. The citation is: Kouli A, Torsney KM, Kuan WL. Parkinson’s Disease: Etiology, Neuropathology, and Pathogenesis. In: Parkinson's Disease: Pathogenesis and Clinical Aspects. Stoker TB and Greenland JC (Editors), Codon Publications, Brisbane, Australia. 2018. ISBN: 978-0-9944381-6-4. http://dx.doi.org/10.15586/codonpublications.parkinsonsdisease.2018.ch1. This is an open-access publication under the terms of the “Creative Commons Attribution-Non Commercial 4.0 International (CC BY-NC 4.0) License” which permits sharing, reproducing and transforming the material in any medium or format, provided the original work is cited appropriately and it is not used for commercial purposes. This thesis also includes modified excerpts of an open-access review article. The citation is: Kouli, A., Horne, C.B., Williams-Gray, C.H., 2019. Toll-like receptors and their therapeutic potential in Parkinson’s disease and α-synucleinopathies. Brain, Behavior, and Immunity. https://doi.org/10.1016/j.bbi.2019.06.042. This is an open-access publication under the terms of the “Creative Commons Attribution-Non Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) Licence” which permits sharing the material in any medium or format, provided the original work is cited appropriately and it is not used for commercial purposes. Furthermore, as per the Elsevier copyright permission guidelines: “Authors can include their articles in full or in part in a thesis or dissertation for non-commercial purposes”.

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/5dfc29d2-caa0-4f32-ada2-e6c66714d965/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

en

Author Identifier

0000-0001-6553-6154
0000-0001-8843-7730

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/297660