Molecular dissection of the enzyme responsible for amyloid-beta protein production in Alzheimer's disease
With increasing incidence of Alzheimer’s disease (AD) and a lack of disease modifying treatments, a rational approach to developing therapeutics is critical. One example is targeting the enzyme that directly generates the amyloid-beta protein (Aβ). The build-up of Aβ in the AD brain occurs early in the disease process. Trials to date, targeting the gamma-secretase (“g-sec”) enzyme have been associated with severe side effects. More selective targeting is required if this enzyme is to be pursued as a therapeutic. During Melissa's honours year, she identified the combination of areas within one component of “g-sec”, the presenilins, involved in Aβ production. I this PhD project, Melissa will use both laboratory experiments and computer modelling to now validate, refine and pinpoint area(s) within presenilins critical for Aβ production. This work will ultimately offer potential targets for designing more selective small molecule therapeutics aimed at slowing down or preventing build-up of pathogenic Aβ.
Methylation-based biomarkers for prodromal Alzheimer's disease
Alzheimer’s disease usually affects older individuals, but hallmarks of the disease begin to be apparent in mid-life. Michelle Lupton will investigate whether chemical modifications of the DNA, called methylation markers in blood, are associated with AD risk. She will also test for an association with brain measures showing very early stages of dementia. These include cognitive assessments and the latest innovations in brain imaging which can detect early disease effects before diagnosis.
This project will test whether DNA methylation markers are an early predictor of whether a person will develop Alzheimer's disease. The identification of a blood sample based biomarker which is easily accessible will enable selection of individuals for drug trials and early intervention therapies, with an ultimate aim of preventing the disease progressing.
Effects of social interventions on stress and inflammatory responses in dementia
The National Gallery of Australia Art Dementia program provides individuals with dementia the experience to engage with others socially and with art in a safe space. However, there is limited quantitative evidence to support broader investment in the program. We aim to contribute to the evidence by examining the stress and inflammatory responses in individuals exposed to the art therapy program using only non-invasive measures. To determine whether the program is beneficial, we will use a cognitive test and carer reports to evaluate changes, and also measure lifestyle factors such as nutritional intake. This will be conducted as an 8-week controlled trial with pre and post measures. A follow up trial will investigate participants using a nutritional intervention to determine if there is an additive benefit. This research is expected to provide valuable insight into the ability of the program to improve quality of life in individuals with dementia.
Realising the potential of remote art centres to support older Aboriginal people and people living with dementia within the context of Consumer Directed Care
Paulene Mackell's PhD is embedded within a project being led by the National Ageing Research Institute. The project is exploring and building on the ways that art centres, located in remote communities are supporting older Aboriginal people and people living with dementia. Approximately a third of artists using the centres are older than 55 and may be eligible to access aged care services. The project will identify and trial new ways for local organisations to work collaboratively in settings where access to services can be limited and the rates of dementia, and other conditions associated with ageing, are higher than the general population. The PhD project will examine how the project’s use of methodology facilitates these opportunities and aims to contribute new knowledge for aged care providers, researchers, funders and policy makers. Overall, it is hoped that the project builds an understanding of what is required to increase culturally appropriate service options in remote Australia for older Aboriginal people, their families, carers and communities.
Using big data to understand the health status, service use, and service pathways of people with less common types of dementia
People with dementia experience high rates of mental and physical health problems. It is important that the health system is prepared to meet their needs. Most research has focused on the health of people with Alzheimer’s disease, the most common type of dementia. Less is known about the health status and health service use of people with less common types of dementia, including frontotemporal dementia and dementia due to other disorders or diseases. This study will use linked data from a large sample of people with less common types of dementia in NSW to describe patterns of mental and physical health problems and how they use health services. Findings will be compared to the NSW general population and to other more common dementia syndromes. This will inform the development of specific strategies that will allow health services to better meet the needs of people with less common types of dementia.
Cognition-focused Interventions Design, Evaluation, and Reporting (CIDER): A repository of cognition-focused intervention trials targeting older adults
People of all ages, but particularly older people, fear losing their memory, and this anxiety is in part fuelled by commercial marketing of unregulated techniques (e.g. ‘brain training’) which claim not only to enhance cognitive functions (memory, thinking, attention), but even to prevent dementia. While many of these products are easily found (e.g. online, app downloads) there is no equivalent access to the relevant evidence base in a trustworthy form that is also user friendly for the broadest possible range of stakeholders (e.g. researchers, policy makers, dementia consumers, health professionals, entrepreneurs, journalists, the general public). Our project addresses the science-implementation gap with a unique international collaboration to build a world-first freely accessible web-based searchable repository of information about cognition-focused interventions for older persons, covering the spectrum of health to dementia: CIDER (Cognitive Intervention Design, Evaluation, and Reporting).
What do they know about dementia? Determining community knowledge about dementia
Our conversations with communities show that people feel that to become a dementia friendly community, all members of the community need to know about dementia. This project is surveying the wider Tasmanian population to see what people do know about dementia using a valid and reliable survey instrument that has been used in previous studies. So far the research team has surveyed over 350 people across most parts of Tasmania. The research team will also hold focus groups to talk with people from various communities. These conversations are about which areas of community education people think are important and how they think this education would best be delivered. The findings of this study will help educators, community members and peak bodies develop education to teach people about dementia.
Investigating motivational changes in frontotemporal dementia and Alzheimer’s disease
Apathy is a common symptom of dementia and may result in someone withdrawing socially and/or neglecting self-care activities. It is currently unclear what causes apathy, or why symptoms may be displayed differently in frontotemporal dementia (FTD) or Alzheimer’s disease (AD). Whilst apathy is generally assessed as a single symptom, recent research indicates that apathy may be multidimensional, with three subdomains - affective, behavioural and cognitive - that affect the way symptoms are displayed. Emma's PhD research aims to investigate the brain regions associated with apathy and whether different areas are affected differently in FTD and AD. First, a behavioural assessment of apathy will be conducted. This will be followed by neuroimaging to determine which areas of the brain are involved in apathy in FTD and AD. Finally, a combination of clinical and experimental behavioural assessments will be conducted with participants and carers. This will determine the impact of apathy on day to day life and relationships, and which symptoms are linked to which apathy subdomain. Results will be applied to develop a multidimensional apathy assessment tool specific for use in dementia to correctly diagnose FTD and AD. Further, understanding apathy will assist with provision of appropriate person-centred care to manage apathy in dementia, and reduce the impact on carers.
The therapeutic potential of cannabidiol (CBD) in mouse models of Alzheimer's disease
The approved medications for Alzheimer's disease (AD) do not stop or prevent the disease from progressing and have limited efficacy, highlighting the need for new and more effective AD therapies. AD is characterized by the deregulation of two proteins, amyloid-β (Aβ) and tau, which is accompanied by extensive inflammation, oxidative stress, and degeneration of the brain. Cannabis sativa, marijuana, is a complex plant that is currently being investigated for its potential therapeutic benefits, particularly in neurodegenerative and inflammatory disorders such as AD. Cannabidiol (CBD) is a non-psychoactive constituent of this plant that has shown to reduce inflammation, oxidative stress as well as Aβ and tau-related effects in vitro. The research team propose to investigate the preventative effect of CBD in AD transgenic mouse models relevant to Aβ and tau. They will treat the mice for 6 months before observing their cognitive performance in various tests, which will be followed by examining the brain tissue for AD-relevant pathologies, including Aβ, tau, oxidative and inflammatory markers. It is hypothesised that CBD will prevent the development of cognitive deficits and AD-relevant pathologies in these mice thereby providing preclinical data for the therapeutic potential of CBD as a new AD treatment.
This feasibility study aims to enhance services currently available to care recipient/carer couples living with early-stage dementia attending a general medical practice or a Queensland Health memory clinic. Healthcare professionals working in the two settings have been trained and supported to deliver a structured education and support program to the couples. The five program sessions focus on identifying/managing dementia related changes, establishing a support network, and encouraging social outlets. The couple document how they will live well with dementia in their SHARE plan, which they update and share with their family and friends. Post-intervention evaluations show that couples that have completed the program are very satisfied with program content and location, feel better informed, are planning for the future, and have expanded their support networks. These are significant findings as older people living with dementia often try to manage alone until a crisis occurs, at which point choices are limited.
How do microglia-synapse dynamics change with Alzheimer's disease?
Historically, microglia are referred to as the immune cells of the central nervous system. This project explores the emerging role of microglia in facilitating changes to neuronal connections, synaptic plasticity or the ability of the brain to remodel throughout the lifespan in response to a changing environment. Using state of the art imaging techniques this project explores microglia-synapse interactions in real-time, to elucidate their role in Alzheimer’s disease. Using our innovative approach to understanding the role of microglia at the synapse, our findings may represent a major advance in our understanding how synaptic connections are regulated and are likely to be fundamental in informing any therapeutic manipulation of microglia to induce neuroplasticity in models of health and disease.
Heat shock proteins in Alzheimer's disease
It is now well known that Alzheimer’s disease involves the aggregation and deposition of proteins within the brain, which may suggest the importance of molecular chaperones in the manifestation of these protein-aggregate diseases. Heat shock proteins (HSP’s) play an important role in cellular homeostasis by repairing and refolding damaged or stress denatured proteins. HSP’s, known for their chaperoning ability, have now been associated with Alzheimer's disease pathogenesis and its potential as a pharmacologically modulated target in Alzheimer's disease treatment. Jessica is investigating the activation of heat shock protein 72 in the brain as a potential therapy against the cognitive decline associated with Alzheimer’s disease. Furthermore, the somewhat epidemic of obesity and Type 2 Diabetes within our society has been linked to a higher risk of cognitive decline. Jessica is therefore also investigating the role of a Western Diet and its resultant insulin resistance on the progression of Alzheimer’s disease and the treatment effects of heat shock protein 72 activation.
Harnessing the power of exosomes to understand Alzheimer’s disease
Every year, the number of people living with Alzheimer’s disease increases due to our aging population and the lack of effective drugs currently available. This increase is a global problem and if we are to successfully intervene we need a clearer understanding of what’s driving the disease. Alzheimer’s disease is characterised by impairment in clearance of toxic molecules from brain cells which leads to cell death and ultimately memory deficits in affected individuals. We recently discovered a novel relationship between these toxic molecules and tiny vesicles trafficked around the brain, called exosomes. This project aims to determine the role of exosomes in Alzheimer’s disease with goal of understanding their contribution to disease progression. This study will reveal the potential that exosomes hold as drug targets and will provide the field with a new perspective on the onset and progression of Alzheimer's disease.
Development and pilot testing the Dignity in Care Survey for acute and subacute care settings
Health and aged care services strive to provide ‘person-centred’ or ‘consumer-directed’ care, but there is no agreed tool used across health and aged care to measure these concepts. The purpose of this research study is to develop a questionnaire that could be used to measure patients’ and carers’ experience of receiving care that is consistent with the 10 Principles of Dignity in Care. These 10 Principles are short, simple and powerful expressions of how health and aged care consumers interpret the 'person-centred' and 'consumer-focused' models of care. The research team will develop three versions of a Dignity in Care Questionnaire: a version for use by older people (including people with dementia) who are admitted to hospital; a version for use by their carer (i.e., their family/friend/advocate); and a version for use by health care staff. The validity and reliability of the Dignity in Care Questionnaire will be evaluated and if acceptable, will be recommend for use in Australian hospitals.
Does sleep predict future memory decline? A five-year follow-up study of a community-based cohort of older adults
This study proposes to follow-up a sample of community-based older adults, five years after their initial involvement in a baseline study that collected information on sleep and memory measures. The aim of the current project is to determine whether aspects of sleep are associated with memory decline over time. Study involvement will include assessment of sleeping patterns by wearing an activity monitor (similar to a Fitbit) on the wrist for two weeks to obtain an objective measure of sleeping patterns; completing questionnaires about perceived sleep quality; and undertaking an assessment of memory and other aspects of thinking. The analyses will examine whether sleep at baseline, or change in sleep patterns from baseline to follow-up, are associated with memory decline over time. This study is proposed as a pilot study which is hoped will provide the basis for applying for further research funding for a larger-scale project. The results will have important implications for understanding memory decline in ageing, improving the early detection of AD, and providing the opportunity for developing memory interventions targeting sleep.
Dementia Stigma Reduction (DESeRvE): A randomised controlled trial to reduce dementia related stigma in the general public
Dementia is a stigmatised condition and dementia-related stigma is undoubtedly harmful with the ability to cause negative effects on people with dementia and their carers. Stigma can lead to low self-esteem, isolation and poorer mental health in people with dementia, and increased burden in caregivers. Stigma can also prevent people from seeking help. This results in people missing out on timely diagnosis and the utilisation of health and social services. Timely diagnosis is beneficial to people with dementia and carers as it provides time to better plan for future care, delays institutionalisation, reduces costs to the health system, and leads to timely treatment and slower cognitive decline. It is therefore vital to develop programs to reduce the stigma of dementia. In this study, we are developing and evaluating the short-term effectiveness of an online intervention programme (Dementia Stigma Reduction (DESeRvE)) aimed at the general public to reduce dementia-related stigma.
Identifying early molecular changes underlying familial Alzheimer’s disease
To reduce the enormous social and financial impacts of Alzheimer’s disease (AD) we must understand why and how AD occurs and be able to detect the pathological process (through biomarkers) so that intervention is possible before brain damage becomes too great. There is no firm consensus on what begins the decades long progression to AD. New technologies allow precise engineering of genomes and detailed gene expression analysis of tissues. However, there has not yet been any detailed analysis of the early brain changes in a fAD mutation model. The least studied fAD gene is SORL1. It is uncertain whether fAD mutations in SORL1 are dominant. My project will be to introduce fAD mutations into zebrafish SORL1 and then analyse their effects on transcriptome expression in young brains. This will also suggest biomarkers for early detection of the pathological processes leading to AD and will resolve the question of SORL1 fAD mutation loss or change of function.
The pathway to diagnosis: Experiences of caregivers of people with dementia
This study will provide valuable, up-to-date data on the experiences of caregivers on pathway to dementia diagnosis; one of only a few studies of its kind internationally. The findings of this research will provide important insight regarding gaps which may exist in provision of dementia care and services in the pre-diagnosis phase. Identifying such gaps will help to determine where improvements in care and future research are needed most. The research gives voice to the concerns and preferences of consumers to inform the development of strategies to reduce delays and overcome the barriers to obtaining a timely diagnosis. Understanding the path that people travel to the point of diagnosis will allow service providers and policy makers to target efforts to ensure that diagnosis is coordinated and supported.
Involvement of SIRT3 and related energy metabolite changes in the Alzheimer brain
Free radicals caused damage to lipids, proteins and DNA are hallmarks of Alzheimer’s disease (AD). This damage causes energy generation to falter and therefore damaged mitochondria can lead to impaired memory and cognitive function over time. Given that this is a important hallmark of AD, and neurons are especially sensitive to insults that result from energy depletion and free radical damage, proteins such as sirtuins which are involved in the cell’s response to oxidative stress as well as energy metabolites such as NAD which are used as substrates for these proteins and others involved in DNA repair, may play a key role in the pathogenesis of neurodegeneration. Therefore, the aim of this study is to look at sirtuin protein and related energy metabolite changes in control and AD post mortem brain tissue and potentially uncover new avenues to preserve or boost energy levels to maintain brain bioenergetics.
Exploration of the associations between cognitive performance and dual-tasking, gait and physical performance in community-dwelling older adults and individuals with Alzheimer's disease
Alzheimer’s disease is a condition that affects memory and the ability to reason. It is recognised that mild cognitive impairment, that is decreases in memory, ability to learn, or short attention span, is a strong predictor of developing Alzheimer’s disease later on in life. Early intervention has been shown to lead to better quality of life for people with Alzheimer’s disease and therefore screening for risk factors of Alzheimer’s disease, such as mild cognitive impairment, could be expected to lead to better management and slower progression of the condition. The purpose of this study is to explore brain, physical, and cognitive function in individuals with or without memory complaints, and individuals with diagnosed Alzheimer’s disease. The work is expected to help identify possible treatment targets, and refine screening tools to detect the signs of impending cognitive decline earlier and thus help enable improved care to individuals with Alzheimer’s disease.