Sustaining exercise to enhance cognition: A feasibility study
Over the past two decades, research has consistently shown that older adults undertaking regular physical activity have better memory and thinking skills and a lower risk of dementia. However, in studies where people are allocated to exercise interventions, there are not always observed effects on memory and thinking. One contributing factor to the varied results across previous studies may be the lack of high-intensity exercise delivered within interventions, which has been shown to provide significant benefits to the brain. In addition, although supervised exercise studies in older adults usually report good attendance, they often don’t contribute to long-term changes in exercise habits. Prior to undertaking a large-scale study that would address the above, it is necessary to conduct a smaller, ‘pilot’ study. We will determine the feasibility of delivering high-intensity exercise coupled with behavioural change techniques and education to older adults, with the ultimate aim of enhancing brain health. The programme will include behavioural change techniques and education, with the objective of giving individuals the tools required to change their long-term exercise habits.
Driving in people with mild cognitive impairment (MCI): current practice and perspectives amongst people with MCI, occupational therapists and medical practitioners
Research has shown that many people living with mild cognitive impairment have only minor driving problems, whereas other people demonstrate unsafe driving behaviours such as difficulty positioning the vehicle within the correct lane. However, it is not known what driving recommendations are made by the health professionals who see these people when they attend memory and driving clinics. It is unclear what proportion of these people are suspended from driving, recommended to continue driving or referred for on-road driving assessments. This project will involve an audit of medical records that are written by doctors working in these clinics to find out what driving recommendations they make. People living with mild cognitive impairment, doctors and occupational therapists will also be interviewed to obtain different perspectives about current practice and gaps. We will address the gaps identified by developing a tool to assist with decision making about fitness to drive. It is anticipated that this will lead to improved safety for all road users and reduce negative outcomes for people living with mild cognitive impairment who demonstrate the ability to continue driving safely.
Respite care and transition to permanent residential care for people living with dementia and informal carers: Mind the Gap!
People living with dementia often have specific care needs that are provided (mostly) by informal carers (that is, family and/or friends). There may come a time, however, when the physical and/or emotional demands of caregiving are no longer manageable, hence the importance of supportive residential respite care without transition to permanent care. Respite can be defined as a pause, or an interval of rest, from the duties of caring, but doesn’t necessarily require a physical distancing from the person living with dementia. For the carer, transition of a person living with dependency to permanent care, can be laden with a combination of guilt, confusion and relief, but this will vary from person to person. This project aims to co-design a new and novel approach to short-term residential respite care and transition into permanent care in conjunction with people living with dementia and their carers, residential care staff and management. This project is exploratory and, as such, it is unclear what the exact program will look like. The project is designed to generate ideas on what might work, rather than testing a known intervention. A prototype program will be generated from the co-design sessions, followed by the testing of assumptions related to the program, to identify how to make the program better.
Investigating stress-related therapeutic targets for Alzheimer’s disease in human neuronal cells
Stressful experiences are all around us. These experiences can make us more likely to develop Alzheimer’s disease and, if we have Alzheimer’s disease, can speed up its progression. So it’s vital to understand how stress impacts the brain in Alzheimer’s disease. To do this in the laboratory, we are using brain-like human cells from adult donors to model Alzheimer’s disease. We are investigating how these cells respond to stress hormones called glucocorticoids, which are released when we’re stressed. So far our work has suggested that cells in the brain may respond differently to stress hormones in people living with Alzheimer’s disease. It has also revealed that some aspects of these stress hormone responses may be helpful, and others harmful. This new study will dig deeper into stress, the brain and Alzheimer’s disease. What happens inside the brain-like cells which model Alzheimer’s disease when they are exposed to stress hormones? When, how and why can stress hormones can be beneficial or damaging? By answering these questions we hope to enable development of drugs and environmental interventions which target stress hormones to decrease risk for Alzheimer’s disease and improve the lives of all of us as we age.
Consumer and clinician led priority setting for the NNIDR MEDicines and DEMentia (MEDDEM) National Research Action Plan
This project aims to identify the top 10 unanswered quality use of medicines (QUM) questions for people living with dementia. These questions will be generated and prioritised by Australians living with dementia, carers, and health care providers (clinicians). QUM means using medicines safely, effectively and when they are needed to get the best possible health outcomes. We will determine priorities using a multi-step research process. A national survey conducted with stakeholders and championed by a stakeholder Steering Group will determine what questions participants have had about medicines and dementia. These questions will be assessed to determine if there is already an ‘answer’ – has high quality research already been done? A second questionnaire followed by a workshop will prioritise the unanswered questions, resulting in a top 10 list. In the past, health research questions have been led by drug companies or researchers, with little involvement of clinicians and consumers. We aim to determine which questions are important to people living with dementia and their care team, to prioritise research in these areas and ensure that outcomes of research are directly relevant to the care of people living with dementia. This will lead to improving how medicines are used which in turn will improve health outcomes in people living with dementia.
"Cage vs Age": Development of an innovative nanotechnology to halt the spread of hyperphosphorylated Tau protein in Alzheimer's disease
Alzheimer's disease is the most common cause of dementia, accounting for 60-70% of all cases. Current Alzheimer’s disease medications only alleviate symptoms and do not modify the underlying mechanisms that cause the disease. Consequently, finding an effective therapeutic for Alzheimer’s disease is of critical importance. One major contributor to the spread of Alzheimer’s disease within the brain is the transmission of abnormal forms of a protein called tau. In this process, abnormal tau is released from diseased brain cells and taken up by neighbouring healthy brain cells, triggering the misfolding of the normal tau inside those cells. Thus, Alzheimer’s disease progressively spreads throughout the brain. Nanoparticles are tiny balls that can be engineered to package drugs and deliver them precisely to diseased tissue inside a patient, thus enhancing a drug treatment’s efficacy and improving the outcomes of patients. This project aims to harness the properties of unique nanoparticles found inside bacteria by re-engineering them into a novel nanotechnology that can be utilised to treat dementia. These naturally-occurring nanoparticles will be altered into tiny drug carriers that selectively target and disrupt tau pathology, halting the progression Alzheimer’s disease inside the brain. To reach this goal, I will combine a set of novel tools and techniques found in protein engineering, drug delivery, pharmacology and neurobiology. This research has the potential to provide a disease-modifying treatment that would be of significant benefit to the millions of individuals living with Alzheimer’s disease.
Evaluating the feasibility and effectiveness of a novel discourse intervention to improve everyday communication in people with dementia
Communicating and staying socially connected with others is important to people with dementia, yet there are very few evidence-based interventions to help people living with dementia to retain skills needed for everyday conversations and to engage socially. This study will adapt a highly novel intervention approach that has been trialled with other neurological conditions, such as after stroke, in hope of improving the everyday communication and quality of life of people with dementia. This structured, yet interactive, approach aims to improve how people organise and structure their everyday talking, for example, when giving opinions, sharing personal stories, recounting events, and explaining procedures, all of which occur in daily conversations. If found to be effective, the treatment protocol refined through this study will have significant implications and be widely disseminated to speech pathologists. This study hopes to enable better access to evidence-based communication interventions that have potential to make a meaningful difference to the social connectedness and wellbeing of people living with dementia.
Preventing recurrent hip fractures: are people with dementia prescribed evidence-based treatments?
People living with dementia are at an increased risk osteoporosis and hip fracture compared to people without dementia. However, recent reports suggest people with dementia are less likely to be prescribed evidence-based treatments for osteoporosis to prevent recurrent fractures. Our aim is to determine patterns and predictors of receiving guideline-recommended medications for osteoporosis after hip fracture in people with and without dementia, and to determine whether use of guideline recommended medications prevents subsequent hip fracture. We will conduct a large multinational cohort study across Australia, UK, US and Hong Kong. This will be achieved by building a common data model based on a previously funded project via the Dementia Australia Research Foundation. We will include people discharged from a hospital for hip fracture between 2012 and 2018. Dementia will be identified through ICD-10 codes from hospitals and medication dispensing data. Osteoporosis medications after hospital discharge will be captured from pharmacy dispensing data. Rehospitalisation for hip fracture will be captured from ICD-10 codes. By utilising large population-based databases in four countries we will produce generalisable results with a high likelihood of impacting policy and practice. Advocates will be engaged throughout the project to maximise the benefits of this research directly to people living with dementia.
The impact of modifiable risk factors on cognitive decline and Alzheimer’s disease dementia
As the search for a cure for Alzheimer's disease dementia remains unsuccessful, it is important to consider other ways to delay or prevent it. A range of modifiable risk factors, such as obesity, physical inactivity, low mood, disrupted sleep, social isolation and low cognitive engagement have been found to be related to cognitive impairment and dementia risk. However, most studies have only examined the contribution of these risk factors to cognitive dysfunction and dementia risk individually. As these risk factors are highly related to each other, a more comprehensive understanding of the contribution of modifiable risk factors to cognitive dysfunction and dementia risk would be achieved by examining the combined effects of these risk factors. The aim of the proposed project is to examine the additive or interactive contributions of each modifiable risk factor to determine their effect on cognitive dysfunction and dementia risk. The contribution of key genetic risk factors, such as the apolipoprotein E (APOE) E4 allele, to this relationship will also be explored. The results of this project will have the potential to inform the design of future multi-modal lifestyle intervention trials that aim to prevent or delay dementia.
Clarifying the relationship between alcohol use and dementia
Whilst heavy alcohol use has been identified as a key modifiable risk factor for dementia, previous studies have shown that low to moderate alcohol use is beneficial when compared with both abstaining and heavy alcohol use. However, previous research has limitations. With alcohol use increasing among older adults, further research is needed to clarify the relationship between low to moderate alcohol use and the risk of dementia. Using large-scale data combined across 15 international studies (48,965 people), the current project aims to investigate the relationship between different patterns of alcohol use and dementia in adults aged over 65 years. The use of large-scale data will allow an unprecedented examination of the relationship between patterns of alcohol use and dementia, and how these may differ according to key clinical and demographic characteristics. This project will contribute to evidence-based recommendations on the number of standard drinks associated with minimal dementia risk. These practical recommendations will have a clear benefit in terms of dementia risk reduction in the wider community.
Optimising daily activity patterns for brain health in older adults
Achieving enough physical activity and sleep, and limiting sedentary behaviour (e.g. prolonged sitting), improves brain function and reduces dementia risk in older adults. These three behaviours coexist to make up the 24-hour day, and to increase time spent in one of these, time must be taken away from another. We still do not know the best combination of these behaviours within a 24-hour time period for cognition or dementia risk in older adults. This project will investigate how brain health and function in older adults is affected by how much time is spent sleeping, engaging in physical activity or being sedentary across the 24-hour day. This information will be collated to understand “best day” patterns for optimal brain health and function in healthy older adults. The findings will contribute to the development of an interactive app which will predict how changing time use (e.g. reducing sitting time and increasing sleep) affects an individual’s brain health and function.
Investigating the effect of Factor Xa anticoagulant on dementia risk
Individuals with an irregular heartbeat or recurrent blood clots are often prescribed drugs that thin the blood long-term. Some of these treatments include drugs inhibiting FXa, an important protein of the blood clotting process. However, FXa is known to be capable of performing multiple tasks besides regulating clots. In platelets, a type of blood cells that are important in wound healing and clot formation, FXa is capable of controlling ADAM10, a protein responsible for managing the breakdown of Amyloid Precursor Protein (APP) into harmless fragments. Reduced function of FXa may potentially cause incorrect processing of APP into Amyloid Beta (Aβ) peptides, a sticky toxic substance that drives the development of Alzheimer's disease. As platelets are the main producer of APP in the blood, we first aim to investigate, in test-tube settings, the processing of APP in healthy platelets after exposure to FXa inhibitors. Next, we will give anti-FXa drugs to mice, and then analyse their blood for signs associated with Aβ production. Finally, we will compare the blood of patients on long-term FXa inhibitor and other anticoagulants for levels of Aβ peptides. As direct FXa inhibitors are now widely used, we must understand how these drugs may increase the risk of dementia.
In-vivo synaptic correlates of cognitive reserve
Given that the incidence of Alzheimer’s disease increases with age, it has been estimated that delaying dementia onset by 5 years would decrease the prevalence of late-onset dementia by 50%. In this project we will investigate the biological basis of Cognitive Reserve, a protective property of the brain known to delay dementia onset, but whose underlying mechanisms remain a mystery. Because the cognitive deficits in Alzheimer’s disease are strongly associated with a loss of synapses – the point of communications between neurons – we believe that Cognitive Reserve is first implemented at the synaptic level as a way to preserve neuronal communication. In this project we will take a state-of-the-art microscopy approach to directly visualise the loss of synapses inside the brain of a living Alzheimer’s disease animal model and the compensatory and regenerative events that follows that might serve as the basis of Cognitive Reserve. Given that therapeutics targeting the formation of amyloid pathology have failed in numerous clinical trials, we will focus on the protective mechanisms of the brain to cope with pathology rather than on those leading to pathology in the first place. The outcomes of this project may be instrumental in developing effective therapeutics harnessing these protective mechanisms as a way to delay the onset of dementia.
Personalising care of people with dementia through music: Development and testing of a training program for aged care workers
People living with dementia often experience mood disturbances such as depression or agitation, which can have a big impact on quality of life and carer stress levels. The use of drug-based treatments for these mood disturbances are often undesirable because of side-effects, so the development of cost-effective non-pharmaceutical treatments is highly important. There is considerable evidence that music can have a positive influence on the mood of people living with dementia. However staff buy-in and knowledge are significant barriers to the effective use of music programs in aged care facilities in Australia. This project will merge the experience of Western Sydney University and HammondCare to develop an online training program for aged care staff and home-based carers of people living with dementia. The course, to be developed in close partnership with end users and people with lived experience of dementia, will help caregivers to understand the potential for music to be used as part of individual care plans to manage mood-related symptoms in dementia.
Enhancing the TBK1-p62 axis as a therapeutic strategy for frontotemporal lobar degeneration
Frontotemporal lobar degeneration (FTLD) is the most common cause of dementia in younger people. Autophagy is a natural process where damaged proteins and mitochondria (tiny specialised structures responsible for energy production) are removed from the cell. In FTLD, autophagy is reduced, which leads to a build-up of damaged proteins (TDP-43) and damaged mitochondria in brain cells, causing them to die. Autophagy requires a protein called p62, which is activated by another protein,TBK1. In 3-4% of FTLD cases a change in the TBK1 gene leads to a mutated TBK1 protein being produced. Researchers don’t yet know how mutant TBK1 proteins cause FTLD. However, we found that two mutant TBK1 proteins did not activate p62, which reduced autophagy and caused TDP-43 to build-up in the brain. We will now test whether other mutant TBK1 proteins fail to activate p62 and cause TDP-43 and mitochondria to build-up. Our study will help researchers to understand exactly how TBK1 gene mutations cause FTLD. Increasing TBK1 levels may reduce the build-up of TDP-43 and damaged mitochondria in the brain and this could be beneficial in FTLD. Therefore, we will also test potential therapeutic compounds to find those that enhance TBK1 levels.
Harnessing habits to increase physical activity in people with Mild Cognitive Impairment and Subjective Cognitive Decline.
For older people experiencing decline to their memory and thinking skills, keeping physically active is important to maintain brain health and reduce risk of dementia. Despite this, over 80% of older Australians do not do enough physical activity in their daily lives. To date, interventions to help people increase their physical activity levels have involved setting goals, planning and self-monitoring, which are challenging for people with thinking and memory difficulties. Recent research suggests that automatic, every-day habits play an important role in maintaining physical activity levels over the long-term. The current project aims to target these habits to help people with mild cognitive impairments create healthy, automatic habits of regular physical activity, that are easy to maintain over the long-term. To achieve this, we will develop and pilot the Harnessing Automatic Behaviours Intervention Trial (HABIT), a personalised physical activity behaviour change intervention for people with mild cognitive impairment. The results of the HABIT pilot will be used to guide a larger community trial of the intervention, and produce practical advice for people experiencing thinking and memory declines about how to use habit to increase their everyday physical activity to levels that are beneficial for brain and cognitive health.
Personalising dosage regimens of medicines in Alzheimer's disease
Alzheimer’s disease is a medical condition affecting the brain. However, recent evidence suggests that our body is also affected by Alzheimer’s disease and as such, may absorb or metabolise medicines differently. Compared to those who do not have the disease, people living with Alzheimer’s disease tend to have more medical conditions and consume more medicines. Therefore, they are more likely to experience undesirable effects from medicine(s) or, as the body does not handle medicines in the same way as someone without Alzheimer’s disease, suffer the effects of under or overdosing. Prescribing practices can be improved if we understand what changes actually happen in our body when we have Alzheimer’s disease. Our project uses cutting-edge technology to thoroughly screen for the changes in a mouse model of Alzheimer’s disease as well as in human tissues. This information will be used to generate pharmacokinetic profiles of medications of interest. The profiles will promote medication safety and effectiveness in people with Alzheimer’s disease by helping doctors to decide the best treatment, with the least number of medicines, at the right dose.
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 examined the genes turned on in individual cells in post-mortem brains donated by patients with Alzheimer’s disease and found in human brains a type of microglia similar to the plaque-eating microglia in mouse brains. We also found similarities in the functional roles between mouse and human Alzheimer’s microglia in terms of the ability to eat up synapses, the connections between neurons.
We next tested whether our predicted drugs that can switch microglia into the protective plaque-eating type. We found that using our drugs we can control a group of genes, and importantly the functions, in microglia-like cells made from human stem-cells. We have started to test directly the involvement of the molecule HIF1 in controlling the microglial switch in mice modelling Alzheimer’s disease.
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. Using a novel mechanism thought to be causing the nerve cell loss that results in FTD, this project used live imaging to find a starting point for dysfunction to try and prevent it from happening. Using mice that model FTD through a mutation of the protein TDP-43, live imaging was used to pinpoint, in real time, the earliest disease-causing changes at the synapses. Researchers then identified that these changes could potentially be prevented by selectively applying low-intensity stimulation to the brain. Changes in neural plasticity was one of the earliest changes in FTD mice, suggesting that preventing these changes may also prevent neuronal dysfunction. Brain stimulation also significantly altered the onset of FTD in mice with the mutant TDP-43 protein. Finally, stimulating brain regions with alleviated dementia-type behavioural traits in those mice. Findings have improved our understanding of FTD, and may inform a possible pathway to improved, earlier diagnosis, and future therapeutic treatments and intervention options.
Chennupati Jagadish AC
Use of brain organoids and artificial intelligence for understanding dementia.
This project presented a novel strategy for diagnosis and treatment of Alzheimer’s disease using an innovative approach that combined technologies in stem cell research with artificial intelligence (AI). The stem cell component of this project saw the development of ‘brain organoids’ or ‘mini-brains’ from stem cells taken from people living with Alzheimer’s disease as well as individuals unaffected by the disease. The stem cell derived brain organoids were used to model brain function ‘in-the-dish’. Major findings from this research were 1) the identification of differences between Alzheimer’s disease and non-diseased neurons, and how alterations affect the communication between brain neurons, 2) new insights into how microglia, the brain’s immune cells, function in Alzheimer’s disease and 3) development of innovative bioengineering technologies to measure how neurons generated from stem cells and cultured in a dish can form networks and send signals to each other, which somewhat mimics brain connectivity. This novel project has contributed to a greater understanding of Alzheimer's disease.