Taylor, Joseph
(2024)
Physiological phenotyping of human frailty.
PhD thesis, University of Nottingham.
Abstract
Frailty is an age-related syndrome characterised by an enhanced vulnerability to adverse health outcomes compared to the non-frail state. However, the physiological phenotype of frailty is poorly understood. This thesis aimed to provide novel insight into the frailty phenotype, thus identifying physiological targets for further research into mechanisms driving frailty progression. A deep physiological phenotyping study was performed in older (aged 65-91 years) non-frail, pre-frail and frail females with no overt disease. Frailty status was defined using the Physical Frailty Phenotype criteria: weakness, slowness, exhaustion, weight loss and low physical activity. Participants were deemed non-frail if no criteria were present, pre-frail if one or two criteria were present, or frail if three or more components were present. Assessments of physical function, neuromuscular characteristics and multi-organ MRI were performed.
In Chapter Three, resting cardiac MRI revealed no differences in structural or functional cardiac parameters between older non-frail, pre-frail and frail females, indicating physiological differences within the cardiovascular system in resting supine volunteers do not differentiate the frail versus non-frail phenotypes.
Chapter Four highlighted lower skeletal muscle volume of the leg and lower isometric strength, functional quality (isometric strength normalised to thigh muscle volume), work output and neuromuscular control of the knee extensors in pre-frail and frail versus non-frail females. For example, dominant leg skeletal muscle volume was lower in pre-frail (1979 ± 177 cm3/m2) and frail (1893 ± 169 cm3/m2) individuals compared to non-frail females (2162 ± 175 cm3/m2; non-frail vs pre-frail: P = 0.026; non-frail vs frail: P = 0.011). Knee extensor isometric strength was also lower in pre-frail (80 ± 18 Nm) and frail (64 ± 14 Nm) females versus non-frail females (105 ± 23 Nm; non-frail vs pre-frail: P = 0.011; non-frail vs frail: P = 0.002). No differences in muscle fat fraction or visceral adipose tissue volume were observed.
Chapter Five highlighted lower regional grey and white matter volumes and differences in cortical folding in frail versus non-frail volunteers. For example, lower grey and white matter volumes were evident in the postcentral gyrus (P < 0.001) and frontal pole (P < 0.001) in frail versus non-frail females, which may be related to lower proprioceptive and cognitive performance in frail individuals. In regression analyses, grey and white matter volumes in motor function- and cognition-related brain regions were strongly associated with physical function measures. For example, grey matter volume in the lateral occipital cortex (T = 4.74; P < 0.001) and precentral gyrus (T = 4.49; P < 0.001) exhibited the strongest associations with knee extensor work output. Functional and haemodynamic measures of the brain were no different between groups.
Chapter Six integrated physiological and physical function data from experimental Chapters Three to Five with correlation analyses. Significant correlations were observed between several cardiac, body composition and brain morphometry measures, such as positive correlations between grey matter volume and leg muscle volume (r = >0.35; P < 0.01), suggesting the phenotype of frailty may be underpinned by interactions between multiple organs. Reinforcing the findings from Chapters Four and Five, the strongest associations with physical function were observed in body composition and brain morphometry characteristics. For example, dominant leg fat fraction and white matter hyperintensity volume showed significant negative correlations with knee extensor work output (r < -0.35; P < 0.05 for both comparisons).
The robust multi-organ measurement techniques adopted in this thesis provided novel insight into the physiological phenotype of human frailty. Novel assessments of several organ parameters were performed, (e.g., cardiac T1 mapping and oxygen utilisation of the brain), thus improving understanding of the multi-organ phenotypic traits of frailty. Integration of physiological and physical function data revealed that the physiological phenotype of frailty is primarily characterised by alterations and interactions within the skeletal muscle and brain. This thesis has identified a research pathway to inform on the design of longitudinal studies to determine the physiological changes underlying frailty progression.
| Item Type: |
Thesis (University of Nottingham only)
(PhD)
|
| Supervisors: |
Greenhaff, Paul
Francis, Susan
Gladman, John |
| Keywords: |
Frailty; Physiological phenotyping; Physiology of aging |
| Subjects: |
R Medicine > RB Pathology |
| Faculties/Schools: |
UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences |
| Item ID: |
79454 |
| Depositing User: |
Taylor, Joseph
|
| Date Deposited: |
11 Dec 2024 04:40 |
| Last Modified: |
11 Dec 2024 04:40 |
| URI: |
https://eprints.nottingham.ac.uk/id/eprint/79454 |
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