Protecting axon-glial interactions to guard against dementia
Alzheimer’s disease and vascular dementia can be associated with vascular related brain damage, often caused by brain cells being deprived of oxygen. White matter regions of the brain are particularly susceptible to this type of injury. They contain the long, thin nerve cell processes that act like the electrical wires of the brain, and the specialist insulating cells called oligodendrocytes, that wrap and insulate the nerves, and provide them with energy and nutrients. This project will study the interactions between nerve cells and oligodendrocytes under normal and low oxygen conditions. It will determine how oligodendrocytes die and determine whether blocking this pathway to enhance oligodendrocyte survival can improve nerve cell health in low oxygen conditions. Additionally, this project will examine individual oligodendrocytes in order to understand which nerves they associate with, how they regulate nerve cell function to facilitate learning and memory, and how this is affected in dementia.
How does stress impact pathological processes in Alzheimer's disease?
Brain changes associated with stress may increase risk for Alzheimer’s disease, or make it worse. This makes the stress hormone system an exciting target for new drugs, but more work is required to understand how such drugs might work. This study will investigate how the stress hormone system impacts production and accumulation of a molecule, amyloid beta, which builds up abnormally in brain cells during Alzheimer’s disease. This study will also determine whether this happens ‘vice versa’, so that amyloid beta abnormalities change the sensitivity of brain cells to stress. By performing these experiments, we hope to lay the groundwork for new therapies for reducing risk for Alzheimer’s disease and slowing its progression.
Entrainment of brain oscillations to improve inhibitory function in people with MCI
Inhibitory control, a key aspect of executive cognitive control, declines early in the neurodegenerative processes that ultimately lead to dementia. It appears that changes in the brain networks are responsible for a decline in inhibitory control in individuals with mild cognitive impairment (MCI), a preclinical stage of dementia. It has been suggested that non-invasive brain stimulation (NiBS) is a powerful tool to improve cognitive function in people with the AD. Here we will investigate whether the application of NiBS can improve inhibitory function in people with MCI. The aims of the project are (1) to investigate the efficacy of NiBS on inhibitory function in people with MCI, and (2) to reveal the underlying neurophysiological mechanisms in inhibitory processing changes induced by NiBS on brain networks. Thus, the project will answer the question of whether NiBS can ameliorate declines in inhibitory control by altering the functioning of specific brain networks.
Developing and evaluating an online Healthy Brain Ageing psychoeducation and cognitive training intervention for older adults with Mild Cognitive Impairment
The Healthy Brain Ageing team at the University of Sydney’s Brain and Mind Centre has developed and tested a multi-faceted, face-to-face information and brain training program for older adults at higher risk of developing dementia. Our seven-week ‘Healthy Brain Ageing’ program can improve memory, depression symptoms and sleep quality. We aim to translate this program to a web-based format, thus increasing its accessibility and suitability to a broad range of older adults. We will redesign the program, taking into account specific needs of older adults with cognitive difficulties (e.g. navigating the Internet, engaging activities etc.). We will then scientifically evaluate whether the online program is effective and feasible compared to a ‘waitlist’ control group who will receive the program later on. This project represents an opportunity to develop and evaluate a cost-effective, accessible and deliverable intervention to reduce the impact of cognitive decline in older adults ‘at risk’ of dementia.
Therapeutic songwriting to support relationship quality among community dwelling people living with dementia and their family caregivers: A proof of concept randomised controlled trial
This project for community-dwelling people living with dementia and their family carers aims to examine the potential of group songwriting as a means for improving their social connection, mental health and wellbeing, and positive change in quality of life for both. Group songwriting, facilitated by a registered music therapist, is an innovative process involving social interaction, mental stimulation and emotional exploration with others in a similar situation to create original songs. The songwriting process is expected to help families and couples living with dementia to explore personal resources and challenges, and may assist them to continue living together in a loving and mutually supportive relationship for as long as possible. Songs written during the project will be performed and recorded to increase public awareness and understanding about what it is like to live with dementia.
Consumer co-creation of an e-health dementia risk profiling tool: exploring benefits and harms
Would you want to know your risk of dementia? How can this be communicated to you in a meaningful, non-distressing, and engaging way, which will motivate you to make changes to your lifestyle and health risk factors to reduce your dementia risk? This project addresses these questions by conducting focus groups with consumers to explore their attitudes towards knowing personal dementia risk and collaboratively designing an interactive online personal dementia risk profiling tool. We will test the resulting risk profiling tool in a trial with people at-risk of developing dementia to assess whether it facilitates an accurate understanding of risk, and its impacts on psychological distress and engagement in behaviours to reduce risk. The risk profiling tool could be later used in primary care, ehealth interventions, and dementia prevention programs, to empower people at risk of dementia to take action to reduce their modifiable risks and lessen the impact on society.
Evaluating social engagement services for older adults in community care: Role of social networks in cognitive decline
Current treatments for dementia are effective in only a subset of patients, and for these individuals it only manages to temporarily halt symptom progression. A ‘cure’ would involve reversal of a complex cognitive and non-cognitive syndromes, and likely require psychosocial changes early on in an individual’s life. Here, we aim to see if rich and meaningful social networks play a significant protective role in memory decline associated with old age. The proposed studies will inform future social engagement services through their evaluation of current social services offered in community care (e.g., meals on wheels, intergenerational interaction activities) and will form a new evidence base on how to best structure social networks in order to improve an individual’s quality of life.
Stabilising the retromer protein coplex with molecular chaperones for Alzheimer's and Parkinson's diseases
Many neurodegenerative diseases, including Alzheimer’s and Parkinson’s, are inherently disorders of protein homeostasis. Targeting of neuronal proteostasis for the treatment of neurodegenerative diseases and dementia is thus emerging as an area of significant interest for pharmaceutical development. But our understanding of these pathways, in neurons in particular, and our ability to pharmacologically manipulate these pathways is severely limited. One of the central mechanisms controlling neuronal proteostasis is the transport of proteins within the endolysosomal membrane controlled by a molecular machinery called the retromer complex. Retromer dysfunction has been strongly linked to neurodegenerative diseases, and such defects in cells and animal disease models can be rescued by the over-expression of retromer. Recent studies have confirmed that a retromer-enhancing small molecule chaperone can reverse both amyloid β and α-synuclein accumulation in neuronal cell models.
This project seeks to determine the molecular mechanism of chaperone interaction with retromer, and being to identify new molecules with greater specificity and activity. The implications will be a better understanding of the molecular basis of retromer stabilisation, providing a novel platform for the validation of retromer as a therapeutic target for neurodegenerative diseases and leads towards the development of future drug design.
Together but alone: caregiver grief and loss in dementia syndromes
Dementia is defined by loss – loss of specific brain cells due to diseases like Alzheimer’s disease cause changes in a person’s abilities and thinking skills. The losses that accompany dementia produce a form of grief that starts before the person dies and is expressed by family caregivers as loss of relationships, lifestyle, and future plans. Most research exploring grief in dementia has focused on Alzheimer’s dementia (AD) rather than other types of dementia, such as frontotemporal dementia (FTD). FTD is defined by behaviour change, which is known to result in higher levels of caregiver burden. To understand the contribution of grief to caregiver burden, this research aims to look at differences in grief experiences for spousal caregivers of people with AD and FTD. This will form the basis of interventions to support caregivers of people with different types of dementia with the goal of reducing overall caregiver burden.
Safe and just futures for people living with dementia in residential aged care ('Safe and Just Futures')
People living with dementia experience disproportionate rates of institutional violence in Residential Aged Care Facilities (RACFs). ‘Safe and Just Futures’ engages people living with dementia, care partners, lawyers, advocates, RACF regulatory bodies and services around stories and solutions for a safer and more just dementia care. It develops workable recommendations for more appropriate and effective legal responses to protect and enhance quality of life for people living with dementia in RACFs. This action research project takes an approach that combines dignified, respectful and non-discriminatory reparation and support for individual victims with large-scale reform to the RACF regulatory frameworks and practices and public hearings of past and historical abuses. The project seeks to:
Promote reforms to regulatory frameworks and RACF practices to promote safer and more just care of people living with dementia; and
Recognise and remedy harms experienced by people living with dementia and others affected by these incidents.
Ageing brings an increased vulnerability to cognitive decline and dementia. However, what places some individuals at a higher risk to develop dementia is not well understood. Recent studies suggest that obesity is associated with brain inflammation and significantly increases the likelihood to develop ageing-related cognitive decline. This project will determine whether obesity-induced cognitive decline is driven by increased activation of microglia, the brain immune cells, and if by suppressing the activity of these cells cognitive dysfunction can be improved. This study will significantly advance our understanding of the role microglia have in ageing-related cognitive decline and the development of dementia, particularly in the context of obesity. Findings from this project aim to provide a novel target for therapeutic interventions that may benefit individuals with dementia.
Investigation of age-related alteration to hippocampal elemental and biochemical homeostasis and neuro-vascular function, as a means to identify new therapeutic strategies to minimise or delay dementia onset in the elderly
Australia is facing a crisis from the enormous health care costs associated with Alzheimer’s disease and dementia. New research into pathways that contribute to the disease are urgently needed, to identify lifestyle strategies or therapies to prevent, minimise or delay dementia. Of all the organs, the brain has the highest energy demands, which makes blood vessels, the suppliers of vital energy and nutrients to the brain, essential to healthy brain function. Several researchers have proposed that damage to blood vessels in the brain, may upset finely balanced biochemical relationships, potentially driving the progression of dementia. However, identifying when and where such events occur has been difficult. My aim in this project is to use newly developed imaging techniques, made possible with incredibly bright synchrotron light, to study changes in biochemical and metal levels that occur inside brain cells after damage to blood vessels.
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.