http://theses.ncl.ac.uk/jspui/handle/10443/101 Tue, 03 Feb 2026 19:50:33 GMT 2026-02-03T19:50:33Z http://theses.ncl.ac.uk/jspui/handle/10443/6386 Title: Investigating the effect of age-associated mitochondrial alterations in intestinal tumour development Authors: Whitehall, Julia Claire Abstract: During ageing there is clonal expansion of mitochondrial DNA (mtDNA) point mutations in colonic epithelial crypts, leading to defects in mitochondrial oxidative dysfunction (OXPHOS). In addition, OXPHOS dysfunction has been shown to be caused by mtDNA mutations in human colorectal adenocarcinomas. However, the effect of age-related mtDNA mutations has on intestinal tumour development remains unknown. To address this question, a mouse model (PolgAmut/mut), which has accelerated accumulation of mtDNA mutations leading to OXPHOS deficiency in the intestine with age, was crossed with an inducible mouse model of intestinal adenoma development (PolgAmut/mut/Lgr5-creER/Apcfl/fl). These mice have a shorter life expectancy due to accelerated tumour growth compared with control mice (PolgA+/+/Lgr5-creER/Apcfl/fl) (unpublished data). The aim of this thesis was to investigate which molecular pathways are altered by age-associated OXPHOS dysfunction in normal intestine, and whether these provide an advantage during intestinal tumour development. Whole transcriptome, unbiased, RNA sequencing was performed on small intestinal (SI) crypts from PolgAmut/mut and PolgAmut/mut mice to identify differentially expressed genes. Results showed upregulation of expression of genes in the de novo serine synthesis pathway (SSP) and serine-uptake and metabolism. Upregulation of these genes was also seen in SI adenomas from PolgAmut/mut/Lgr5-creER/Apcfl/fl mice and was confirmed at the protein level by immunohistochemistry. SI adenoma organoid ex vivo culture from PolgAmut/mut/Lgr5- creER/Apcfl/fl and PolgA+/+/Lgr5-creER/Apcfl/fl mice allowed functional analyses to be performed. Extracellular flux analysis and metabolomics confirmed a reduced oxidative respiratory capacity and an upregulation of de novo serine synthesis in the PolgAmut/mut/Lgr5- creER/Apcfl/fl organoids; which displayed a resilience to serine and glycine starvation compared to controls. These data show an upregulation of the SSP and generation of onecarbon units in normal intestinal crypts in response to OXPHOS dysfunction. These pathways provide substrates for anabolic and antioxidant pathways, providing a selective advantage for tumour growth and survival. Description: PhD Thesis Tue, 01 Jan 2019 00:00:00 GMT http://theses.ncl.ac.uk/jspui/handle/10443/6386 2019-01-01T00:00:00Z http://theses.ncl.ac.uk/jspui/handle/10443/6191 Title: What can gait analysis tell us about dementia and its subtypes? : an integrated study of brain and behaviour Authors: Mc Ardle, Ríona Miriam Abstract: Discrete gait characteristics are associated with select cognitive functions, potentially reflecting underlying neural processes. Therefore, different dementia subtypes may have unique signatures of gait impairment, reflecting their different underlying disease pathologies. As such, gait may be a useful tool to aid differential diagnosis of dementia disease subtypes, such as Alzheimer’s disease (AD) and Lewy body disease (LBD), which includes dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). A large structured review undertaken as part of this thesis highlighted a lack of studies investigating a comprehensive range of gait characteristics in well-classified dementia subtypes. Thus, the primary aim of this thesis was to investigate the potential of discrete gait characteristics to differentiate dementia disease subtypes in both laboratory and free-living environments. There was a particular emphasis on discriminating AD and DLB, as clinical similarities between these subtypes can lead to misdiagnosis and incorrect management and treatment of disease. 110 people participated in this observational cross sectional study. Participants with mild cognitive impairment and dementia related to AD (n = 36), DLB (n = 30) and PDD (n = 15), and controls (n = 29) underwent gait assessment in controlled laboratory environments. Additionally, body-worn monitors continuously collected gait data over seven days in free living environments, providing information about spatiotemporal gait characteristics, and the quantity, variability and pattern of habitual walking activity. Participants completed a battery of cognitive tests and, associations between gait and cognitive variables were examined across all testing environments. Selective patterns of gait impairment differentiated AD and LBD subtypes in the laboratory, while PDD could be discriminated from all disease subtypes in free-living environments. When considering patterns of gait impairment across different walking bout lengths, there was promising evidence that gait could also differentiate AD and LBD in free-living environments. Gait-cognition associations appeared dependent on disease subtype, potentially reflecting underlying pathology. Additionally, differences in habitual walking behaviour between controls and dementia subtypes was found and associated with motor disease severity, balance confidence and executive dysfunction. This thesis is the first to describe gait in well-characterised dementia disease subtypes in both laboratory and free-living conditions. It provides novel evidence to support a role for quantitative gait analysis and discrete characteristics as clinical biomarkers to aid differential diagnosis and further enhance understanding of the complex relationship between gait and cognition Description: PhD Thesis Tue, 01 Jan 2019 00:00:00 GMT http://theses.ncl.ac.uk/jspui/handle/10443/6191 2019-01-01T00:00:00Z http://theses.ncl.ac.uk/jspui/handle/10443/5734 Title: Tracking the development of social learning Authors: Machin, Jennifer Jane Abstract: Background Developmental shifts in social learning (SL), from selective copying to overimitation, are common in childhood. These differences appear to be both age- and taskdependent. Multiple explanations have been proposed, including participants’ understanding of the task goal, affiliation with the demonstrator, and the influence of developing abilities, (memory, theory of mind). Much research focuses on young children or adults, with little understanding into how these behaviours develop during middle childhood and adolescence. Little is known about how participants attend to demonstrations and whether this affects their task performance. This thesis investigated the role of multiple tasks, developing abilities, and attention to demonstrations in children and adults, with the aim of understanding the SL process from beginning to end, and to determine whether a developmental trajectory of copying strategies was present. Methods Three studies examined the influence of task types, developing abilities, and attention to a demonstration in typically developing participants aged three to 45. Four tasks were used: a puzzle box, a tool-building task, a puzzle board, and a colouring task. Eye-tracking was used in order to examine the relationship between participants’ attention to the demonstration and their task performance. Experiment three investigated participants’ understanding of task goals and the demonstrator’s intentions. Results Minimal differences in eye-tracking patterns between overimitators and selective copiers were observed. Differences in copying strategies were observed between age groups, and appeared to be linked to memory development but not theory of mind. Participants’ interpretation of task goals influenced their own task performance. Copying fidelity was task-dependent across all age groups. Conclusions Overimitation does not appear to be influenced at the “attention phase”, but instead may be driven by participants’ memory ability and understanding of task goals. Caution should be used when using one SL task in isolation, as copying behaviours varied across tasks in the same participant groups. Description: PhD Thesis Mon, 01 Jan 2018 00:00:00 GMT http://theses.ncl.ac.uk/jspui/handle/10443/5734 2018-01-01T00:00:00Z http://theses.ncl.ac.uk/jspui/handle/10443/5240 Title: Mitochondrial dysfunction in the pathogenesis of osteoporosis Authors: Hipps, Daniel Abstract: Osteoporosis is a skeletal disease, characterised by reduced bone mass and altered microarchitecture, with subsequent loss of strength, increased fragility and risk of fragility fractures. Hip fractures alone cost the NHS £2 billion per year and have associated high morbidity and mortality. The pathogenesis of falling bone mineral density, ultimately leading to a diagnosis of osteoporosis is incompletely understood but the disease is currently thought to be multifactorial. Humans are known to accumulate mitochondrial mutations with age and mounting evidence suggests that this may be intrinsic to changes in phenotype with advancing age and pathogenesis of age-related disease. Mitochondrial mutations have been shown to occur from the age of 30 years in tissues such as colon, which interestingly correlates with commencement of decline in bone mineral density. This work has demonstrated the presence of mitochondrial DNA mutations in individual human stem cells and respiratory chain deficiency in human osteoblasts for the first time using novel techniques including single-cell PCR, flow cytometry and imaging mass cytometry. Work with the Polgmut/mut mouse model which acquire mitochondrial mutations at an enhanced rate, has demonstrated significantly higher levels of osteoblast respiratory chain deficiency compared to age matched wild type controls. This was associated with significantly reduced osteoblast population densities, reduced bone formation and increased osteoclast activity. Through these novel techniques, this work has demonstrated that underlying mitochondrial pathology directly affects mesenchymal stem cells and osteoblast potentially contributing to osteoporosis which will lead the way for development of new treatment modalities. Description: Ph. D. Thesis. Fri, 01 Jan 2021 00:00:00 GMT http://theses.ncl.ac.uk/jspui/handle/10443/5240 2021-01-01T00:00:00Z