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http://theses.ncl.ac.uk/jspui/handle/10443/98
2024-02-04T18:48:47ZDoes a senescene-like phenotype in neurons contribute to brain ageing and neurodegeneration?
http://theses.ncl.ac.uk/jspui/handle/10443/4177
Title: Does a senescene-like phenotype in neurons contribute to brain ageing and neurodegeneration?
Authors: Fielder, Edward Peter
Abstract: Senescent cells accumulate in the body with age, and drive organismal ageing and tissue dysfunction. Senescence is not a simple growth arrest, but is accompanied by a host of phenotypic changes, including the generation of pro-inflammatory molecules, and is maintained by a network of auto- and paracrine reinforcement. Senescence is now also understood to occur in post-mitotic cells, including neurons – contrary to the former definition of senescence occurring exclusively in proliferating cells. This is called the senescent-like phenotype. While senescent cells can be seen to increase with age, little is known about their relation to cognitive function with age or pathological states such neuro-inflammation.
Using a model of chronic inflammation, the nfkb1-/- mouse, I investigated neuro-inflammation, cognitive function and the frequency of senescent-like neurons with age and treatment with the COX-2 inhibitor ibuprofen. Increasing microglial proliferation and neuro-inflammation could be observed, together with deficits in spatial memory. This was accompanied by an increase in the numbers of senescent-like neurons. Increased accumulation of persistent DNA damage in pyramidal neurons, and a deficit in the generation and propagation of Carbachol induced gamma frequency oscillations, could be seen in the CA3. COX-2 appears to have a role in mediating these effects, as treatment with ibuprofen was effective in ameliorating levels of neuro-inflammation, cognitive dysfunction and senescent-like neurons.
Ageing INK-ATTAC mice were given pharmacogenetic and pharmacological treatments to investigate if these could clear senescent-like neurons. Pharmacological clearance (Dasatinib and Quercetin) was effective in reducing the numbers of senescent like neurons, and these mice showed an improvement in cognitive function, while pharmacogenetic treatment had a lesser effect.
The data presented in this thesis implicate the senescence and the senescent-like phenotype in neuro-inflammation and ageing, and in driving the accompanying declines in cognitive function.
Description: PhD Thesis2018-01-01T00:00:00ZDietary intake, B vitamins and health outcomes in the very old : $$b analysis of the Newcastle 85+ study
http://theses.ncl.ac.uk/jspui/handle/10443/4104
Title: Dietary intake, B vitamins and health outcomes in the very old : $$b analysis of the Newcastle 85+ study
Authors: Mendonça, Nuno Miguel Pinho
Abstract: The very old (aged 85 and over) are the fastest growing age group in the UK and most western societies. High incidence of disability and chronic diseases, financial constraints, polypharmacy, hospitalisation, body composition, sensory and gastrointestinal changes place very old adults at increased risk of malnutrition. However, very little is known about the dietary habits and health trajectories in this age group. Further, because one-carbon (1-C) metabolism biomarkers are largely modifiable and have been associated with cognition, cardiovascular disease (CVD) and all-cause mortality, its modulation is of special interest. The overall aim of this PhD thesis was to provide an accurate snapshot of the dietary habits of the very old and examine health trajectories with respect to 1-C metabolism biomarkers in a unique cohort such as the Newcastle 85+ Study. Specifically, we aimed to explore the dietary habits of the very old; to investigate the association between folate, vitamin B12 and its status; and to investigate the cognitive decline and mortality trajectories with respect to 1-C metabolism biomarkers. The Newcastle 85+ Study is a longitudinal population-based study of health trajectories and outcomes over 5 years in 845 eighty-five year olds in North East England. Dietary intake was assessed at baseline on two non-consecutive occasions by a 24 hour Multiple Pass Recall. Baseline red blood cell folate (RBC folate), plasma vitamin B12 and total homocysteine (tHcy) concentrations were determined by immunoassays. Cognitive function was assessed at baseline, 1.5, 3 and 5 years with the standardized mini-mental state examination and a battery of attention tests. Mortality was obtained from the Health and Social Care Information Service, UK. A high percentage of the participants did not meet the dietary reference values for energy, non-starch polysaccharides and several micronutrients. Cereals and cereal products were the top contributors for energy, most macronutrients and several micronutrients, including folate. RBC folate and tHcy were associated with better global cognition at baseline but were not predictive of the rate of decline over 5 years. Higher concentrations of tHcy in all participants and plasma vitamin B12 in women were associated with increased risk of all-cause and cardiovascular mortality. This thesis highlights the paucity of data and uncertainties in this age group. Furthermore, it demonstrates a link between 1-C metabolism biomarkers and age-related diseases.
Description: PhD Thesis2018-01-01T00:00:00ZGait as a predictor for cognitive decline in Parkinson's disease
http://theses.ncl.ac.uk/jspui/handle/10443/3725
Title: Gait as a predictor for cognitive decline in Parkinson's disease
Authors: Morris, Rose Elizabeth
Abstract: Cognitive decline and dementia are core features of Parkinson’s disease (PD) with major personal and socioeconomic impact. Identifying individuals at risk of cognitive decline and dementia is vital in order to optimise clinical management and develop novel therapeutics. However, biomarkers for cognitive decline remain a major unmet need. A large structured review undertaken as part of this thesis revealed discrete gait characteristics predicted cognitive decline and dementia in older adults but to date no such study has been conducted in PD. Thus, the primary aim of this thesis was to investigate gait as a clinical biomarker for cognitive decline in PD.
Newly diagnosed PD participants (n=118) and controls (n=184) completed a detailed quantitative gait assessment under single and dual task conditions at baseline. Additionally, a comprehensive battery of neuropsychological assessments were completed at baseline, 18 and 36 months later. Mixed-effects models identified significant gait predictors of cognitive decline over three years. Baseline cognition was also explored as a predictor for cognitive decline. Finally, gait was collected in the free-living environment using a body-worn monitor (BWM) and cross-sectional analysis explored free-living gait-cognition associations.
Original contributions to knowledge were that gait characteristics under single and dual task in an incident cohort of PD predicted decline in discrete cognitive domains over three years. Critically, in comparison to gait, baseline neuropsychological assessment performance did not predict cognitive decline. Additionally, cross-sectional analysis in early PD revealed discrete gait-cognition associations in free-living signifying future clinical utility for gait as a clinical biomarker.
This thesis provides the first evidence for gait as a clinical biomarker for cognitive decline in PD. Discrete gait characteristics may provide a low cost clinical biomarker and make an important contribution to prognostic models of dementia risk in PD.
Description: PhD Thesis2017-01-01T00:00:00ZThe influence of ageing and culture conditions on limbal epithelial cells
http://theses.ncl.ac.uk/jspui/handle/10443/2800
Title: The influence of ageing and culture conditions on limbal epithelial cells
Authors: Hallam, Dean Mark
Abstract: Introduction. The use of limbal stem cells as a cellular therapy has expanded over the last decade. Currently, the success rate of limbal stem cell transplantations is around 76% with advanced donor age being a possible reason for this figure. Medium and oxygen concentration could also have a detrimental effect on the growth of these cells for transplantation. With age the limbus undergoes a topological change which could alter the stem cells surroundings. A mouse model of corneal ageing was also used to complement the human study and avoid culturing and tissue storage artefacts.
Aims. The main aim of this thesis was to assess the effect of age on corneal epithelial progenitor cells. This then led to the question; is the mouse cornea affected by age and can interventions mediate these outcomes? And finally do culture conditions affect the growth of corneal epithelial stem cell containing cultures, and how does this relate to changes to the niche with age?
Methods. Limbal derived progenitor cells were extracted from human corneosclearal disks donated for research. Cells were cultured either in LEM or DKSFM and either in hypoxia (3%) or normoxia (21%). Immunofluorescence, qPCR, TRAP assay, morphological and clonal analysis where used to assess progenitor composition. The mice used were strain B6.129S-Tert, tm1Yjc/J. Old/AL and DR mice were 22 months old, young were 3 months old. Rapamycin treated mice were 16 months old and were treated for four months, starting at 12 months of age. Dietary restriction was implemented for a period of 16 months from 6 months of age, additionally in the mouse eye a DNA damage marker was also assessed, both telomeric and non-telomericly.
Results and Conclusions. Age has a detrimental effect on the ability to culture a limbally derived clonal population. However age did not affect the levels of positive and negative gene expression markers or ΔNp63 protein level. Interestingly the time that corneal tissue is stored for did not affect the ability to isolate these progenitor cells. The growth of cells in hypoxia decreased negative marker KRT3 and senescence marker p21 regardless of culture medium.
In the mouse model, age had a detrimental effect on the cornea with decreased TAp63, increased ɣH2A.X and TAFs. DR however, tended to have a beneficial effect on the mouse cornea. Interestingly rapamycin seems to be detrimental to the mouse cornea, with similarities with the effects of age.
Description: PhD Thesis2015-01-01T00:00:00Z