Characterising and inducing a protective microglia phenotype in human Alzheimer’s disease.
Despite intensive research into Alzheimer’s disease, we still have no cure. Recent studies show a strong genetic association of late onset Alzheimer’s disease to microglia, a critical cell type in the brain essential for proper functioning of nerve cells and removing damage in the brain. We discovered two types of microglia in the brains of mice modelling Alzheimer’s disease. Our data unveiled that one type of microglia protects the brain by removing damage associated with Alzheimer’s, whereas the other show a prematurely aging identity. This project will investigate whether the same types of microglia that we discovered in the mouse also exist in the brains of human Alzheimer’s patients, and whether they play the same role in human disease. Our analyses predicted drugs that can control the switch between the two types of microglia. In this project, we will test whether turning microglia into our newly discovered beneficial type can yield new cellular manipulation technologies for therapeutic intervention to benefit people living with dementia.
Do therapeutically targetable deficits in neuroplasticity drive Frontotemporal Dementia?
Frontotemporal dementia (FTD) is a devastating neurodegenerative disease that is in desperate need of new therapeutic interventions. We have identified a novel mechanism that may be causing the nerve cell loss that causes FTD. Changes to synapses - the specialised structures that allow nerve cells to communicate with each other – may be an early disease-causing event in FTD. TDP-43, a DNA processing protein, is one of the main proteins that have been identified to play a role in FTD. We have revealed convincing evidence that the dysfunction of TDP-43 can lead to the synaptic disturbances that characterises FTD. It is now time to carefully map the earliest changes in synapses and try and prevent these changes from happening. This proposal will use live imaging in real time to pin point the earliest disease causing changes and then try and prevent these changes from happening.
Supporting expression of sexuality by older people with dementia in long-term care from a person-centred care approach.
Dementia causes many changes in people’s lives, including changes to intimate relationships, sex & expression of sexuality. Understanding preferences for expression of sexuality are fundamental in improving physical and sexual health, quality of life and psychosocial well-being for people living with dementia. The project develops and evaluates a tool to improve the care and support of people living with dementia in long-term care settings from a person-centred approach. Knowledge gained from the tool will allow health professionals to extend care provision into a previously neglected area via developing and/or revising guidelines for practice (e.g. care plans and procedures). It implies potential significant improvements in the understanding as well as care practices of health and care professionals towards expression of sexuality so as to enable the facilitation of a care environment that is supportive of the verbalisation and expression of sexual preference, need and desire by people living with dementia.
Investigating the impact of acute muscle injury-induced inflammation on the brain in the elderly.
A serious complication following a fall-related injury and hospitalisation is the onset of delirium, which can also lead to dementia. This occurs when the body’s defences, including the immune system, are in decline. We have previously found a major defect in key immune cells, known as macrophages, which help explains why repair following injury is slower in the elderly. This defect is likely to have profound effects at other sites, such as the brain and may lead to declining cognitive function following acute injury. Yet, few studies have examined the combined effects of declining immune function on injury repair and impact on brain function. This project will examine changes to the brain of young versus elderly hosts following injury and immune targeting therapy. This will determine whether an ageing immune system influences brain function following acute injury and has the potential to identify new avenues for treatment in the elderly.
Protein Changes that Underlie Selective Vulnerability in Alzheimer’s disease.
The aim of this research is to understand why some neurons are particularly vulnerable in Alzheimer’s disease. Determining why some neurons are vulnerable, and conversely why some neurons are protected, provides a unique opportunity to identify the protein changes that are responsible for the development of Alzheimer’s disease. This study will comprehensively profile the pathological protein changes that occur in vulnerable neurons in early stage Alzheimer’s disease. Specific protein changes that appear to be driving vulnerability in Alzheimer’s disease will be identified and additional experiments performed to determine how these specific protein changes lead to neuron death in Alzheimer’s disease. Results from this study will increase understanding about the cause of Alzheimer’s disease and will identify new drug targets for early stage Alzheimer’s disease.
Making sense of hearing-related neurocognitive impairment: The Auditory Ageing and Cognitive Impairment (AUDACIOUS) Pilot Study.
It is well established that older adults with significant hearing difficulties are more likely to experience cognitive decline and dementia. This link between hearing loss and problems with memory and thinking may be due to communication difficulties, that then lead to withdrawal from activities that are good for maintaining brain health. It is thought that managing hearing loss with hearing aids and other hearing health interventions may reduce a person’s future risk of dementia. However, quality evidence for this is lacking. The Auditory Ageing and Cognitive Impairment Study (AUDACIOUS) will examine the extent to which the relationship between poor hearing and impaired cognitive functioning is explained by lower levels of participation in mentally stimulating activities. It will also investigate if use of hearing rehabilitation services and hearing aids protect against decline. The project findings will have important implications for dementia prevention interventions and practice in hearing health.
Estimating the value of informal care provided to people with dementia in Australia.
There are approximately 200,000 Australians providing informal care to a person with dementia. While informal carers spend a significant amount of time on caregiving, the time costs of informal care are often neglected in health policy decisions, including funding decisions. This is often due to the lack of robust methods to place a monetary value on time spent on caregiving. To overcome this problem, the aim of this project is to derive a preference-based monetary value of the time costs of informal care provided to people with dementia, accounting for positive and negative impacts of informal care. This information will ultimately improve policy advice that utilises cost-effectiveness information and will facilitate the inclusion of the time costs of informal care in future economic evaluations of health care interventions. As such, this project has the potential to improve the quality of dementia care across Australia and the services that people living with dementia and their carers receive.
Getting home safely: Phase 1 - Generating agreement on national policies and procedures for reporting a missing person with dementia.
Disease causing dementia can damage areas of the brain responsible for navigation which places people with dementia at greater risk of getting lost even in familiar places. There are currently no guaranteed methods of preventing people with dementia from becoming lost other than 24/7 supervision. Internationally and in Australia there is strong evidence that delaying a search for the lost person increases the risk of finding them injured, deceased or not at all. In the US, Canada and Scotland alert systems are already being used to inform police and the broader community that a person with dementia is lost. The Getting Home Safely Project aims to revise and develop a standardised approach to reporting a missing person with dementia in Australia to improve health outcomes for this vulnerable population. In Phase one we will be working with police, carers and people with dementia to develop recommendations for this new approach.
A cognitive-mobility stress test to detect MCI and risk of conversion to dementia.
A difficulty for doctors is that not all people with cognitive problems develop dementia. This study will determine if a simple Cognitive-Mobility Stress Test can distinguish between people with subjective cognitive complaints or mild cognitive impairment. It will also provide data for a larger project aimed to predict risk of developing dementia.
The Cognitive-Mobility stress test involves performing a cognitively challenging task whilst walking. We hope that for the clinician, such a simple, inexpensive and non-invasive test will assist with risk stratification and in decision making for further assessment and management. For the individual, better knowledge of prognosis will reduce anxiety and assist in making preventative lifestyle changes and decisions for the future.
Closing the evidence-practice gap in young onset dementia care: a pilot implementation trial.
Although people with young onset dementia (under 65 years at symptom onset; YOD) have been eligible for the National Disability Insurance Scheme (NDIS) since 2016, many have reported problems with accessing support that meets their needs. Research by our team established guidelines for service delivery, but no work has been conducted to bridge the gap between this research and clinical practice. This study aims to improve the knowledge and competence in YOD service provision among NDIS Planners, who sit at the coal-face of assessing needs and developing formal support plans. We will determine whether a multi-component education and mentoring strategy can effectively improve the practices of NDIS planners, encourage innovative and meaningful collaboration with aged and community service providers, and promote best outcomes for people with YOD and their families.
Spatial convergence of dementia and cardiovascular disease risk: evidence to inform policy and practice.
Delivery of more effective preventive intervention efforts to reduce and delay onset of dementia and cardiovascular disease (CVD) events requires knowing where high levels of convergence of dementia and CVD risks occur in communities. As dementia and cardiovascular disease share many of the same risk factors, this project will develop an innovative method to identify clusters and overlap of dementia and cardiovascular disease risk across communities. These risk maps will then be overlayed and contrasted against other available data for built environment and lifestyle factors for the regions in question. These hotspot data have the potential to support targeted, area specific primary prevention activity in health service delivery. Dementia and CVD risk prediction will provide the first rigorous evaluation of future risk of dementia and CVD at the individual level, and will enable clinicians, Public Health Networks and policymakers to design tailored health promotion strategies as well as follow up individuals with higher risk profiles.
The importance of blood pressure and its variability to dementia: an individual participant data meta-analysis from the VARIABLE BRAIN consortium.
High blood pressure is the leading modifiable risk factor for dementia and cerebrovascular diseases. A recent line of investigation in neurology and cardiology indicates that fluctuations in a person’s blood pressure over time are more strongly linked with cerebrovascular diseases than a person’s average blood pressure. This variability in blood pressure also impacts dementia, cognitive function and brain health, however, there have been few studies on this topic. Our aim is to test the hypothesis that fluctuations in blood pressure are associated with dementia and cognitive decline, and secondly, whether the use of certain blood pressure drugs can promote better brain health. To achieve our aims we will bring together researchers from North America, Europe, Asia and Australia, analysing data from 14 studies with information on cognitive function and blood pressure (total=43,219 persons). By thoroughly investigating blood pressure and brain health in this manner, we will help inform decisions on the best strategy to reduce dementia risk.
Use of brain organoids and artificial intelligence for understanding dementia.
In this project, we present a novel strategy for diagnosis and treatment of Alzheimer’s disease (AD) using an innovative approach that combines technologies in stem cell research with artificial intelligence (AI). The stem cell component of this project is to develop ‘brain organoids’ or ‘mini-brains’ from stem cells taken from people living with AD as well as individuals unaffected by the disease. The stem cell derived brain organoids will essentially model brain function ‘in-the-dish’. We will then apply computational and AI-based analyses to identify key functional differences between normal and AD brain organoids and predict stimulation parameters that may promote ‘normal’ brain function. These studies are the first of their kind in combining cell biology and AI computational approaches to study and find treatments for AD.
Nanotechnology for the diagnosis and treatment of neurodegenerative disorders.
There is currently no treatment to prevent or modify the course of Alzheimer’s disease (AD) and other neurodegenerative dementias. Of the many obstacles to achieving the goal of prevention and cure of AD, we have identified two that can potentially be overcome with the latest developments in nanoscience. Firstly, the challenge of an easily available early diagnostic test can be met by the use of nanoparticles with superparamagnetic properties as imaging agents, tagged with appropriate ligands, for MRI and the newly emerging magnetic particle imaging (MPI). Secondly, nanoparticles, because of their ability to cross the brain’s protective barriers, can be harnessed as drug-delivery systems to deliver novel therapeutic agents directly to the site of pathology in the brain. This collaboration between clinical neuroscience and nanoscience therefore has the potential to transform the diagnostics and therapeutics of neurodegenerative disorders.
An international common data model for improving medicine management for people with dementia and comorbid conditions.
Australia’s Clinical Practice Guidelines and Principles of Care for People with Dementia highlight the importance of providing evidence-based care to improve quality of life, maintain function and maximise comfort. However, clinicians do not necessarily prescribe the same guideline-recommended medicines for people with and without dementia. Indeed, people with dementia are often excluded from randomised controlled trials. Fortunately, recent and widespread availability of electronic prescribing and dispensing data are transforming medicine safety and effectiveness research. We propose to develop the first large-scale international common data model (CDM) specifically for people with dementia. A CDM is a data platform that supports secondary use of linked health data through standardising definitions, terminologies, vocabularies and coding schemes. Using the CDM, we will conduct analyses of linked Australian, Hong Kong, UK and US data to generate new evidence regarding medicine safety and effectiveness for people with dementia. This will help fill a critical evidence gap.
Investigating how presenilin causes neurodegeneration in Alzheimer’s disease.
Memory loss in Alzheimer’s disease results from damage, and ultimately the death of brain cells. The sequence of events that underlies this toxicity is unknown, and understanding this could lead to new drugs. Based on our recent clinical findings, and our new understanding of how Alzheimer-associated proteins might contribute to cell damage, we plan to use laboratory models to establish a new mechanism of toxicity, and trial new therapeutics based on this concept.
Ensuring safe and appropriate hospital discharge prescribing of opioids for people living with dementia.
Pain is a common symptom among people living with dementia. Opioid analgesics are often prescribed for pain at hospital discharge. However, opioids have been associated with a range of side-effects including constipation, delirium, falls, trauma and death. People with dementia may be at higher risk of medication-related harm and also prescribed effective pain relief less often compared to people without dementia. The decision not to prescribe opioids at hospital discharge reduces the risk of side-effects but increases the risk of inadequate pain management.
This study aims to investigate opioid prescriptions on hospital discharge and the risk of rehospitalisation and death in people living with dementia. It is a retrospective study linking diagnoses, medications, re-hospitalisations and death. The primary outcome will be time to rehospitalisation or death. The aim and implications of this research is to inform future strategies and recommendations to improve pain management and reduce the risk of opioid-related harm in people with dementia.
Financial vulnerabilities in younger onset dementia: insights for targeted interventions.
People with dementia have a higher risk of being financially exploited, and may also have difficulty managing their money. These financial issues have especially serious consequences for people with younger-onset dementia, as they are usually affected at a stage in their lives where they may still have significant financial responsibilities (e.g. paying mortgages, supporting children, running businesses). However, little is known about the different types of risk factors for financial exploitation and mismanagement in these individuals. Through a series of questionnaires and interviews with family members and tests in people with younger-onset dementia, this project will identify changes in cognition and behaviour that give rise to increased financial exploitation and mismanagement. By understanding what causes these financial problems, we can work to develop better ways to minimise exploitation and mismanagement while supporting financial independence in people with younger-onset dementia.
High-frequency sampling of cognition in clinically normal adults at genetic risk of Alzheimer’s disease using mobile applications.
Detecting the earliest signs of memory problems is critical for identifying individuals at-risk for dementia so that they can be given the opportunity to sign up for clinical trials and make lifestyle changes. Accurately measuring memory change is hard as memory can vary from day-to-day. Most studies measure memory annually, which is problematic because it assumes that individuals are in a similar state of mind every year (not fatigued, not stressed). One alternative is to increase the number of times an individual is tested to get a more accurate estimation of their memory. Unfortunately, many studies cannot implement this approach, as studies do lengthy and expensive tests in a clinic. Using two smartphone apps that we developed, we aim to determine the feasibility and reliability of high-frequency memory assessments. These apps have the potential to be one of the first of their kind to be implemented across large Alzheimer’s studies.
The influence of cerebrovascular disease in dementia with Lewy bodies.
Dementia with Lewy bodies is a common type of dementia, and shares symptoms with Alzheimer’s disease and Parkinson’s disease. Trials have not found any treatments that can prevent deterioration in this condition. There is limited information as to the cause of symptoms experienced and the prognosis. Certain brain changes have been found to be more common in people with dementia. One such change is small bleeds in the brain, called cerebral microbleeds. This study will examine the prevalence and distribution of small bleeds in the brain of people with dementia with Lewy bodies, and explore the effect on symptoms of the condition. The results of the study will improve understanding of the potential influence of cerebral microbleeds in dementia with Lewy bodies, and therefore the clinical condition and management.