Melbourne School of Health Sciences Collected Works - Theses
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ItemCharacterising the ocular phenotype in a murine model of Alzheimer’s disease( 2018)This thesis shows that amyloid beta found in the brain is also present in the retina of a murine model of Alzheimer’s disease. By applying non-invasive retinal techniques, we show that neuronal structural and functional changes occur early in this model and that these are associated with vascular dysfunction. Such retinal hallmarks differentiate Alzheimer's changes from healthy ageing mice and provide evidence that the retina is a viable biomarker for dementia.
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ItemInvestigating the functional roles of microRNA-29b and microRNA-146a in prion diseases( 2018)Neurodegenerative diseases such as Alzheimer’s disease and prion disease are closely related with specific gene and protein dysfunction. Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are characterized by the structural transformation of the cellular prion protein (PrPC) to the disease associated isoform (PrPSc). One hallmark of Alzheimer’s disease is the accumulation of beta amyloid (Aβ) plaques in the brain, resulting from the pathological cleavage of the amyloid precursor protein (APP) by β-secretase (BACE1) and the γ-secretase complex. MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene or protein expression by targeting mRNAs and triggering either translational repression or mRNA degradation. Distinct expression levels of miRNAs, including miR-29b and miR-146a, have been detected in various biological fluids and tissues from prion disease and Alzheimer’s disease patients, as well as in cell and animal models. These miRNAs could be potential diagnostic biomarkers of these diseases, suggesting that investigating the miRNA functional roles and miRNA-target regulation pathways will improve our understanding of the disease regulation networks. The first aspect of the thesis utilized CRISPR/Cas9 gene editing to knockdown miR-29b and miR-146a respectively in a number of cell lines, and cell clones with stable miRNA knockdown were generated. Off-target analysis of the cell clones revealed the high specificity of CRISPR/Cas9 editing of miRNAs. Common and distinct pathways and novel targets of miR-29b were also identified in two cell lines using transcriptome profiling, and potential miR-29b targets in Alzheimer’s and prion diseases were revealed. In the second aspect of the thesis, miR-29b was shown to positively regulate prion protein levels in both miR-29b stable knockdown cell clones and miR-29b overexpressed cells. This regulation is not mediated through miR-29b target SP1 or potential target PPP2CA, which can interact with prion protein or was implicated in prion pathogenesis. miR-29b could further affect PrPSc generation through regulating prion protein levels and potentially affect prion progression. miR-29b was also revealed to regulate APP and BACE1, the two key proteins in Alzheimer’s disease, in in vitro models. Lastly, the dual roles of miR-146a in regulating prion protein and inflammatory pathways were revealed in prion disease. miR-146a can upregulate prion protein levels in both overexpressed and stably downregulated cell models, as well as in miR-146a transgenic mice generated using CRISPR/Cas9 gene editing. miR-146a overexpression also resulted in the decreased formation of PrPSc in prion cell models. The miR-29b/miR-146a-PrP-PrPSc pathways possibly share a similar mechanism involving the interaction of prion protein with Argonaute protein – the key component of miRNA induced silencing complex (miRISC). Prion protein was demonstrated to be a direct target of miR-146a. miR-146a can also target inflammatory regulator TRAF6 in both prion infected cell models and in miR-146a transgenic mice. The findings from this thesis have important implications for the comprehensive understanding of prion disease pathogenesis. The miR-29b/miR-146a-PrP-PrPSc pathways and miR-146a mediated inflammatory pathway are added to the regulation network of prion disease. miRNAs represent novel regulators in prion diseases and other neurodegenerative disorders and hold promise to be future therapeutics to cure prion disease.
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ItemModelling residential aged care in Australia: entry and exit( 2017)Ageing of the Australian population affects the residential aged care system, yet the structure and dynamics of the system remain uncertain. A comprehensive model of residential care based on the individual perspective of residential aged care events is missing. Thus, older Australians, government and care providers have only a limited model of aged care actions. This study uses big administrative unit record data on aged care assessments (ACAP), aged care appraisals (ACFI) and unit record survey data (SDAC) to identify factors associated with aged care events in older persons’ trajectories towards and through residential care. To achieve this goal and broaden understanding of Australian residential care, this study uses the following steps: (1) modelling of the probability of entry to and exit from residential care, with a multi-state model of transitions between levels of care needs; (2) modelling the applications for aged care and approvals for entry to residential care; (3) derivation of transition and mortality assumptions for individual care needs that can be used in a projection model; (4) estimation of life expectancy in residential care based on needs for assistance; and (5) assessing the quality of Australian data on aged care for statistical modelling and projections of residential care demand. The results show that health factors, above all needs for assistance, determine the speed and direction of a person’s progression towards institutional care. Probabilities of aged care events, transition rates and life expectancy estimates, derived in this study, provide a comprehensive picture of Australian residential aged care. These findings are expected to have important implications for residential aged care policies in Australia in terms of having better understanding and more accurate predictive power for the future of aged care.
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ItemPerceptual suppression mechanisms in healthy ageing( 2017)Healthy ageing alters contextual spatial interactions such as centre surround contrast suppression and spatial suppression of motion discrimination. However, the exact neural mechanisms that underlie age related changes to contextual spatial interactions are still elusive. The body of work reported in this thesis explored the perceptual mechanisms behind altered contextual spatial interactions in younger and older adults using psychophysical and neuroimaging methods. Experiment 1 investigated the strength of foveal centre surround contrast suppression under intraocular and interocular viewing for two stimulus durations (40 ms and 200 ms) in younger and older adults. Foveal intraocular center surround contrast suppression decreased with longer stimulus duration whereas interocular surround suppression did not, suggesting contributions from separate mechanisms to these forms of suppression. In addition, intraocular center surround contrast suppression was increased in older adults compared to younger adults; however, interocular suppression was similar in both groups. Experiment 2 studied the effect of orientation of the surround grating in relation to the orientation of the centre grating (surround orientation effect) on centre surround contrast suppression under intraocular and interocular viewing in younger and older adults. Interocular and intraocular centre surround contrast suppression showed different surround orientation effect, and older adults demonstrated unaltered levels of surround orientation effect compared to younger adults under both intraocular and interocular viewing. Experiment 3 measured Gamma Aminobutyric Acid (GABA, the principal inhibitory neurotransmitter of the adult brain) levels in visual cortex of younger and older adults using magnetic resonance spectroscopy. Visual cortical GABA levels were increased in older adults compared to younger adults. In addition, visual cortical Glx (combined estimate of glutamate - the principal excitatory neurotransmitter, and glutamine) levels were reduced in older adults compared to younger adults. Neither GABA levels nor Glx levels in visual cortex correlated with foveal centre surround contrast suppression. The final experiment of this thesis (Experiment 4) investigated the relationship between visual cortical GABA levels and performance on two visual tasks that are hypothesised to be mediated, at least in part, by GABAergic inhibition: spatial suppression of motion discrimination and binocular rivalry. Both younger and adults participated in this experiment as well. Increased visual cortical GABA levels were associated with prolonged binocular rivalry percept durations and reduced spatial suppression of motion discrimination. The experimental frameworks used in the thesis were based on our modern understanding of cortical circuits that are implicated in mediating centre surround contrast suppression, and a neuroimaging technique that could potentially link physiology with behaviour. The novel findings reported in thesis answered some of the important questions related to perceptual surround suppression in younger and older adults. The current findings suggested that healthy ageing differentially affects distinct forms of suppression arising at various levels of the visual pathway, and challenged prior assumptions regarding age related changes to GABA levels within the visual cortex and its association with centre surround contrast suppression and spatial suppression of motion discrimination.
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ItemThe role of Dlk1 in haematopoiesis, leukaemia and angiogenesis( 2017)Delta-Like Homologue 1 (DLK1), also known as Preadipocyte Factor 1 (PREF-1), is a non-canonical EGF-like NOTCH ligand. It is maternally imprinted at the Dlk1-Dio3 imprinted locus, and has been shown to regulate embryonic growth, lipid metabolism and skeletal development. However, the precise role of Dlk1 in haematopoiesis, leukaemia and angiogenesis, processes in which it has been previously implicated, is unknown. We generated Dlk1 knockout and conditional knockout mice and used a constitutive overexpression system via retroviral transduction to specifically study Dlk1 in these contexts. Dlk1 knockout mice showed distinctive phenotype of increased perinatal mortality and growth retardation. In foetal livers, significant expression of Dlk1 was detected in the haematopoietic cells, with higher level of expression in the haematopoietic stem cells compared to lineage positive mature cells, with overall expression decreasing with embryonic age. Dlk1 knockout mice were not significantly different from wild type mice in the mature haematopoietic lineages, but serial competitive transplant assays demonstrated Dlk1 knockout bone marrow cells were inferior to controls in reconstituting lethally irradiated recipient mice in short term haematopoietic reconstitution assays, suggesting that Dlk1 knockout led to a defect in adult short term haematopoietic stem cells. Despite frequent overexpression of DLK1 found in many human acute myeloid leukaemias, constitutive overexpression of Dlk1 did not lead to increase in acute leukaemia or death in reconstituted mice. However, Dlk1-overexpressing haematopoietic cells demonstrated competitive repopulation advantage compared to MIG-transduced controls. Using a retinal model of angiogenesis, Dlk1 was found to be expressed by the pericytes rather than endothelium of newly developing blood vessels in postnatal murine pups, in contrast to the published data. Conditional knockout of Dlk1 in endothelial cells using the endothelial specific Tie2 Cre transgene did not lead to significant abnormality in postnatal retina, confirming that Dlk1 did not have a functional role in the retinal endothelium. These new findings add to our current knowledge of stem cell biology and leukaemia, and the role of Dlk1 in angiogenesis.
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ItemSwallowing difficulties in Friedreich ataxia( 2017)Swallowing is an important biological function reliant on the coordinated interaction between motor and sensory mechanisms. Swallowing dysfunction (dysphagia) is a common sequela of neurodegenerative disease and is associated with significant morbidity and mortality. Dysphagia is associated with malnutrition, dehydration, and aspiration-related pneumonia, and psychological issues such as reduced self-esteem and social isolation. For individuals with movement disorders, dysphagia can be exacerbated by concurrent upper limb impairment, making it difficult to feed independently. Friedreich ataxia (FRDA) is an autosomal recessive condition resulting in a deficiency of frataxin, most commonly due to homozygosity for a GAA trinucleotide repeat expansion in intron 1 of FXN. FRDA manifests in widespread central and peripheral nervous system degeneration, as well as impairment of the cardiac, skeletal, and endocrine systems. Pneumonia (a common implication of dysphagia) is the cause of death in approximately 10% of individuals with FRDA. Whilst dysphagia is a widely accepted feature of FRDA, understanding of the underlying mechanisms and characteristics of dysphagia in FRDA is limited. This project (and resulting thesis) sought to investigate and characterise the swallowing function of individuals with FRDA suspected of having dysphagia, and document the frequency of concomitant aspiration in this cohort. It was also aimed to determine relationship between oropharyngeal dysphagia and clinical markers of FRDA, including age at time of disease onset, disease duration, the GAA repeat size on the smaller (GAA1) and larger (GAA2) FXN allele. Predictors of aspiration in this cohort were also explored. In addition the psychosocial implications of dysphagia were considered using a standardised questionnaire. The study was largely cross-sectional in design, with a smaller group of individuals with FRDA receiving a 12 month follow up to investigate the relationship between dysphagia and disease progression. Results confirm oropharyngeal dysphagia with concomitant aspiration is present in individuals with FRDA and worsens with disease duration and severity. Aspiration in this population can occur at any time during the course of the disease, and therefore swallowing function should be monitored closely. Dysphagia was also shown to significantly affect the quality of life of individuals with FRDA compared to a group of healthy controls. The clinical implications of these findings are discussed along with future directions.
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ItemToward relationship-centred care: patient-physiotherapist interaction in private practice( 2017)Interacting with patients is integral to the practice of physiotherapy. Notably, however, empirically derived knowledge about how physiotherapists interact with their patients is limited, particularly in the private practice setting. In addition, heavily promoted approaches for interacting with patients, such as patient-centred care and the biopsychosocial approach, have been adopted from the medical profession, are not derived from research evidence, and therefore may not adequately reflect how physiotherapists interact with patients in physiotherapy practice. Thus, this qualitative research had two aims: first, to detail how patients and physiotherapists interact in private practice; second, to consider how the research findings related to promoted healthcare interaction approaches. Methodologically, the research incorporated features of both ethnography and grounded theory. Observations of 52 consultations, as well as in-depth interviews with 9 patient and 9 physiotherapist participants, were undertaken. Data comprised field notes and audio-recordings of observations and interviews, and were analyzed iteratively using principles of thematic analysis and grounded theory. The data analysis yielded two central and complementary themes. The theme ‘physiotherapist-led communication’ encapsulates how physiotherapists directed the style and content of communication to achieve clinical goals by providing structure, making decisions, and focussing on biomedical aspects. The second theme, ‘adapting to build rapport’, describes how physiotherapists incorporated adaptive communication such as eye contact, body language, touch, casual conversation, and humour into their interactions with patients. These adaptations were often intuitively enacted, were responsive to individual patient characteristics, and functioned to build rapport. The findings neither clearly correlated to features of patient-centred care nor to the biopsychosocial approach. Rather, the findings portrayed a dynamic integration of clinical and responsive communication that fostered the development of a trusting relationship between patient and physiotherapist. These results extend knowledge of interactions in physiotherapy by providing detailed descriptions of interactional elements that incorporated patient and physiotherapist perspectives. Furthermore, the findings explain how rapport was developed between patient and physiotherapist with trust as an underlying construct. Relationship-centred care and relational notions of trust are discussed as alternative explanations for how patients and physiotherapists interact in private practice. These findings and explanations have the potential to benefit educators, physiotherapists and, by extension, patients, by offering a framework for education and the practice of patient-physiotherapist interactions.
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Item“I knew it was wrong but I couldn’t stop it”: young people talk about the prevention of sexually abusive behaviour( 2016)Child sexual abuse perpetrated by adults in family and institutional contexts is a well-known phenomenon. Child sexual abuse carried out by other children and young people, however, is a comparatively underexplored social problem. Sexually abusive behaviour by children and young people accounts for about half of all child sexual abuse perpetrated. This thesis is about preventing sexually abusive behaviour carried out by children and young people. The aim of the study reported in this thesis was to gather the insights about prevention of young people who had themselves been sexually abusive. That is, working within a critical feminist framework, the researcher asked young people who had abused what could have been different in their lives so that the sexually abusive behaviour did not occur. Interviews were informed by a Critical Interpretive Synthesis, a qualitative systematic review of broad literature regarding sexually abusive behaviour. The insights of the young people were then used to inform suggestions about strengthening the current sexually abusive behaviour prevention agenda. The study involved semi-structured interviews with 14 young people who had completed the Sexual Abuse Counselling and Prevention Program at the Children’s Protection Society in Victoria. The study also involved gathering the reflections of six treatment-providing workers about the insights of the young people. The young people were approached as experts about their experience of being sexually abusive and invited to act as consultants to the research. At the same time, the past abusive behaviour of the young people was not condoned or minimised. Constructivist Grounded Theory was used to guide the analysis of the qualitative data. Five major thematic categories emerged from the interviews with the young people, including: wrestling with gender and sexual attraction; learning about sexuality; having safe relationships; being responded to by others; and conceptualising thoughts and feelings. A further process of data analysis involved comparing and contrasting the insights of the young people with the reflections of the workers, and with the evidence base. This process revealed three main opportunities for preventing sexually abusive behaviour. That is, young people invited action to: make their relationships safe; reform their sexuality education; and help their management of pornography. The opportunities for prevention identified though the data analysis could inform the development of public-health-type initiatives on primary, secondary, and tertiary levels, which could be implemented in local, national, and international contexts. An enhanced prevention agenda would help to protect the right of all children and young people to live free from child sexual abuse.
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ItemActive video game technologies for balance rehabilitation after stroke( 2016)Standing balance deficits are frequent and disabling following stroke; however, optimal assessment and treatment for balance problems remains unclear. The past decade has seen the increasing emergence and clinical uptake of active video game technologies. The purpose of this thesis was to investigate the utility of active video games, in particular the Nintendo Wii, for balance rehabilitation following stroke. A comprehensive, narrative literature review of balance assessment and treatment following stroke was completed. Force platform technologies were found to provide a higher level of objective information on balance performance than clinical tests, but were inaccessible for most clinical settings. The Wii Balance Board (WBB) presented a valid and potentially feasible alternative; however, its clinimetric properties had not been investigated in a post-stroke sample. Active video games, such as the Wii Fit, demonstrated equivalence or superiority in efficacy to more traditional balance training approaches in emerging recent studies, but trials were generally small. Importantly, they provided little insights into feasibility, nor guidance in clinical implementation. A cross-sectional study was conducted to investigate the reliability, validity and feasibility of WBB-based tests of balance in an outpatient stroke setting. Thirty participants were tested on two occasions, one week apart. Five WBB-based standing balance tests demonstrated excellent test-retest reliability (ICC2,k = 0.82 to 0.98) and were poorly to moderately associated (r = 0.04 to 0.61) with performance in four clinical tests of balance and mobility. Minimal detectable change scores, floor and ceiling effects were investigated, to further inform the utility of the WBB variables. These tests were deemed feasible in terms of the time to complete and ease of use. A pilot randomised controlled trial was undertaken to investigate the feasibility and preliminary efficacy of a Wii Fit balance training program in an inpatient setting. Thirty participants (time since stroke, mean (SD) = 25 (18) days), randomised to Wii Fit balance or Wii Sports upper limb training, completed three Wii-based sessions per week over two or four weeks in addition to standard therapy. Feasibility of the Wii training was considered satisfactory based on adherence, acceptability and safety. Greater improvements in balance (i.e., the Step Test and WBB variables) were demonstrated by the Wii Fit balance group. Finally, a comprehensive, theory-based decision-making framework was developed for implementing active video game game-based balance training following stroke. It provides a resource to guide training decisions considering different aspects of the individual, task and environment, underpinned by motor learning theory. This framework may support future clinical and research applications of these technologies. This thesis found the WBB to be a reliable and potentially feasible force platform alternative for low-cost research and clinical use. Wii Fit training was found to be acceptable and safe in an inpatient stroke rehabilitation setting, and the efficacy results can inform the design of future trials. A decision-making framework for active video game implementation is proposed as a potentially valuable clinical resource to guide practice and future research. This thesis provides a substantial contribution to the knowledge in this field and may contribute to improved quality of stroke care in the future.
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ItemBiomechanical and neuromuscular impairments in individuals with gluteal tendinopathy( 2016)Gluteal Tendinopathy (GT) is a typically chronic, recalcitrant cause of lateral hip pain most commonly seen in women aged 40 to 70 years. The condition involves pathology of the gluteus minimus and/or gluteus medius tendons at or above their insertion into the greater trochanter of the femur. Clinically, symptomatic GT presents as pain around the greater trochanter, aggravated during single leg loading in walking and stair climbing, and can have a major impact on function. Based on clinical observation it has been hypothesized that individuals with GT exhibit altered biomechanics and neuromuscular control during single leg loading tasks; specifically increased pelvic drop and hip adduction, which might modify gluteal tendon loading at the greater trochanter contributing to the development and/or perpetuation of the condition. However, despite clinical assessment and treatment for GT often being based on these presumed impairments, little is known about the biomechanical or neuromuscular impairments in individuals with GT. Given evidence of muscle weakness in other lower limb tendinopathies, and that strengthening exercise appears to be an effective management strategy for tendinopathy, Study 1 aimed to establish whether individuals with GT exhibit hip abductor muscle strength deficits when compared to pain-free controls. Interestingly, not only did Study 1 identify hip abductor weakness of the symptomatic hip when compared to the asymptomatic hip and to controls, bilateral hip abductor weakness was identified in individuals with GT when compared to controls. The primary functional role of the hip abductor muscles is to maintain alignment of the pelvis in the frontal plane during single leg loading. Given that single leg stance (SLS) is often assessed visually by clinicians to evaluate hip abductor function, Study 2 aimed (1) to quantify trunk, pelvic and hip kinematics in preparation for, and during, a SLS task in those with and without GT, and (2) evaluate the effect of hip abductor muscle strength on these kinematics. Results from Study 2 showed that in contrast to pain-free controls, individuals with GT exhibit greater lateral translation of the pelvis and hip adduction in preparation for SLS; and more hip adduction and less pelvic elevation during SLS. Hip abductor strength appeared to be a key determinant of these kinematic differences, as when adjusting for strength in our analysis only between-group differences in lateral pelvic shift persisted. As altered kinematics of the hip and pelvis were identified in SLS, and walking is a typically provocative functional single leg loading task for those with GT, Study 3 aimed to evaluate kinematics and kinetics of the trunk, hip and pelvis during walking gait. This was the first study to evaluate walking kinematics and kinetics in individuals with GT using three-dimensional gait analysis. Results showed that, in contrast to pain-free controls, individuals with GT exhibited a greater external hip adduction moment throughout the stance phase of walking as well as greater contralateral trunk lean at the time of the first peak hip adduction moment and greater contralateral pelvic drop at the time of the second peak hip adduction moment. Contralateral pelvic drop was significantly correlated with the first and second peak hip adduction moments, and hip adduction angle with the second peak hip adduction moment in those with GT, providing some insight into potential modifiable kinematic patterns underpinning their greater external hip adduction moment. Finally, post-hoc analysis identified two subgroups with opposite trunk and pelvic strategies within the GT group. Taken together, these findings suggest that evaluation of the trunk and pelvis during clinical observation of gait is warranted in order to identify specific maladaptive gait patterns. A greater external hip adduction moment, identified in Study 3, infers a greater demand on the hip abductor muscles, including the gluteus medius and minimus muscles and the overlying muscles that insert into the iliotibial band (ITB). On this basis Study 4 aimed to evaluate the independent and synergistic characteristics of hip abductor muscle activation during walking using electromyography (EMG). This study highlighted altered muscle activity in the posterior gluteus minimus and middle gluteus medius muscle segments during stance phase in individuals with GT, characterized by greater activity continued into mid-stance, compared to controls. Further to this, individuals with GT exhibited less within-participant variability of the posterior gluteus minimus and less between-participant variability in the anterior gluteus minimus and medius segments and upper gluteus maximus when compared to controls. For both groups, synergy analysis identified two muscle synergies during the stance phase of gait. However, differing levels of contribution from the tensor fascia lata muscle to each synergy was observed between those with and without GT. Taken with a greater external hip adduction moment, modified distribution of activity within the gluteal muscle segments and the tensor fascia lata, which generates tension in the ITB via it’s insertion, has the potential to modify gluteal tendon loading. Compressive forces from the tension in the overlying ITB and the greater trochanter below on the gluteal tendons could have potentially negative tendon effects. Lastly, Study 5 investigated kinematics and kinetics of the trunk, hip and pelvis during a step up task. Similar, to the findings of Study 3, parameters of the external hip adduction moment were consistently greater in those with GT during the stance phase of stair ascent. Based on the patterns of the external hip adduction moment, three subgroups were identified in both the GT and control groups, with individuals with GT 4.5 times more likely to have an external hip adduction moment characteristic of a large impulse, greater lateral pelvic translation and less pelvic obliquity at heel strike than the subgroup most likely to contain controls. The studies outlined in this thesis are the first to report strength, kinematic, kinetic and EMG findings in individuals with symptomatic GT in contrast to pain-free controls. Differences were identified in: hip abductor strength; kinematics during SLS, gait and step up tasks; kinetics during walking and step up; and neuromuscular control of the hip abductor muscles during walking. These findings imply that the gluteal tendons might be experiencing modified tensile and compressive loads in those with GT, with implications for tendon health. Given the cross-sectional study design it is not possible to determine whether these differences preceded or followed GT, but it is possible that restoration of muscle strength and normal kinematics may be beneficial for recovery. However future research is needed to determine whether altered muscle activity, kinematics and kinetics can be changed with conservative treatment and subsequent effects on patient outcomes.