Targetting the IRAP protein to enhance memory in dementia including Alzheimer’s Disease
A very prominent feature of Alzheimer’s disease is the loss of dendritic spines. These spines form the connections between our neurons, or brain cells. These connections are critically important to the way our brain processes and retains information. As we remember events, more of these connections are made between our neurons which in effect physically stores the memory. In Alzheimer’s these connections are destroyed which causes sufferers to forget previous memories while also making it harder for now ones to form.
The lab, which Ben is apart of, has developed a drug series that targets a protein in the brain known as IRAP (Insulin-Regulated AminoPeptidase). By targeting this protein we have been able to improve memory in mice which develop Alzheimer’s disease. Further he has also shown that this drug can increase the growth of dendritic spines between neurons. Research is now directed at examining how this effect takes place
Another key feature in Alzheimer’s is an ability of the brain to properly utilise it’s primary energy source, glucose (a simple sugar). This means that many of the protective mechanisms that exist within the brain may not function effectively thus leading to the damage associated with the disease. The drug is able to increase the uptake of glucose by brain cells and this could explain the beneficial effects it has on memory and dendritic spine number and work is now being performed to examine this possibility.
Randomised controlled trial of 'MAXGOG' intervention for people with mild cognitive impairment
The MAXCOG project is well underway with all the important systems and procedures in place. We have liaised with all of the key stakeholders to produce a manual which will serve as a guide for the provision of the MAXCOG intervention. We have approval from the ethics committees across four health services to process with our study. It has taken time and care to set up relationships across all of the relevant teams and services and we have and have begun receiving referrals from all four sites. We are in the process of bringing Alzheimer’s Australia Vic. counsellors on board in delivering the intervention and have set up an ongoing system of group supervision meetings. We aim to utilise the supervision meetings in order to review the success and appropriateness of the MAXCOG intervention for each client and their supporter. Our evaluation of the MAXCOG intervention will include both quantitative information (from assessment scales etc.) and qualitative information from the clients and counsellors about what they thought was most successful.
The effect of vascular risk factors in dementia onset
This study investigated the effect of vascular risk factors on brain functioning in a group of elderly participants with no memory difficulties. The results of the analysis suggest that older adults with risk factors for cardiovascular disease perform more poorly in tests that measure brain function, compared to elderly participants without any vascular risk factors. This difference was identified on specific cognitive functions, such as inhibition, information processing speed and visuospatial skills, but not on verbal memory or language. The participants were followed for a 54-month period and the results showed that individuals with vascular risk factors exhibited a greater decline over time on the aforementioned cognitive tests. Finally, the study also found that the magnitude of cognitive decline for individuals with three or more vascular risk factors was higher than that measured for those with two or less vascular risk factors. An important application of this work stems from the fact that the vascular risk factors found as having an effect on brain functioning can be reduced through lifestyle changes, such as physical exercise, controlling body weight or reducing smoking. Consequently, the relationship between the presence of vascular risk factors and cognition identified in this study suggests that living a healthier lifestyle can promote brain health.
What Kinds of Support Systems Help People to Remember in Daily Life, Especially as Their Memories Start to Fail?
In Dr Harris' research, she is interested in understanding the nature of memory support that older adults use in their daily lives. One source of support that she is particularly interested in is a long-term partner or spouse, and she is investigating how couples remember together and the kinds of strategies they might use to support each others' memories. She is studying shared remembering in healthy older adults and those who report subjective memory difficulties. She is also interested in external memory supports that people use (e.g. calendars, diaries, iPhones), and how couples share these resources between them. This research will help us understand the kinds of strategies that people can use in daily life to benefit their memory performance.
Decision-making processes in dementia
Making decisions is something we do many times each day. However, we rarely spare a thought for what a complex process decision making is. To make the right decision in a given situation, it is necessary to take in all the available information and weigh up the pros and cons of possible choices, before we then take action.
In patients who have dementia this complex decision making process can be disrupted, leading to behaviours such as being socially inappropriate, not taking care of personal hygiene, impulsive spending or gambling, risk-taking and over-eating. These behaviours can cause harm to the patient and are very distressing for their families and carers.
However, we do not understand exactly what causes decision making processes to break down in dementia. To date, Ms O'Callaghan's PhD project has focused on designing better tests to measure decision making process in dementia, and looking at the brain changes that cause impaired decision making. The novel approaches she has used have looked at these processes have provided important new insights into these complex problems.
The ultimate goal of her research is that through a better understanding of decision making problems in dementia, this will improve our ability to treat and mange these symptoms better in the future.
Can Speech Pathology improve the ability of people with dementia to remember the words they want for conversations
Difficulty thinking of or remembering right words to use in a conversation is a common difficulty for people with progressive aphasia (language difficulties in dementia). This can be frustrating, and will impact on the person’s social interactions and quality of life. Research has found that people with speech pathology treatment people dementia can re-learn words (to name pictures), however, there has been limited investigation into transferring the improvement to conversation.
This study will use speech pathology treatment to treat word-finding difficulties in conversation, with the aim of transferring treatment improvements to everyday communication and therefore improving the quality of life of people with dementia. This study also aims to provide positive evidence for the use of speech pathology treatment in progressive aphasia and dementia.
The role of transforming growth factor beta and tau pathology in frontotemporal lobar degeneration
As part of this project, Dr van Eersel analysed a mouse model of dementia (known as Tau58 mice) that overexpress a human version of the protein tau. She found that these tau-expressing mice display significant increases in brain activity and also display signs of hyperactivity (travel longer and further than normal mice). This therefore suggests that the protein tau can cause excessive excitation of brain cells, resulting in changes in normal behaviour. These mice also develop neuropathological changes in the brain and behavioural characteristics that closely resemble those observed in a human dementia known as Progressive Supranuclear Palsy. Only a limited number of mouse models are available for this particular disorder, therefore our discovery of this new mouse model will help improve research investigating this particular type of dementia.
In a second part of her project, she analysed tau-expressing mice that were genetically manipulated to be unable to respond to the signalling molecule Transforming Growth Factor β (TGFβ). These mice developed a significant worsening of tau pathology-induced motor symptoms, a significant decrease in body weight and had a significantly reduced life span. This therefore suggests that the TGFβ signalling pathway is protective, and that disruptions to this pathway can exacerbate the adverse effects induced by tau pathology. Targeting this pathway to enhance it may therefore be a potential drug therapy for the treatment of frontotemporal lobar degeneration and/or Alzheimer’s disease.
How do our genes affect the development of Alzheimer’s disease?
How do our genes influence the development of late-onset Alzheimer’s disease? To answer this question Dr Mather's research investigates the roles of genetic and epigenetic factors on early markers of dementia, such as memory decline. ‘Epigenetics’ refers to changes in gene function that do not involve alterations of the genetic code. Her research focuses on the epigenetic modification that adds chemical tags to our DNA, known as DNA methylation. The results of my project may help identify people at risk of dementia and help to unravel its causes. Since DNA methylation patterns are potentially reversible by diet and lifestyle changes, the findings from this project may suggest interventions and preventative treatments to slow or prevent dementia.
Improving pain management amongst people with dementia
People with dementia may have pain but unable to report it because of their impaired cognition. Therefore, Dr Hoti has developed a mobile application to assist caregivers and family members identify pain in dementia patients who cannot communicate. The app is integrated in a smart phone which uses the built-in camera to perform automated facial recognition together with certain pain indicators. To his knowledge this is a world’s first electronic pain assessment tool for dementia patients that utilises automated facial recognition technology and mobile platform with the view of reducing user subjectivity and hence more accurately detect pain. The next phase of this project is testing in human subjects and hence validating the electronic pain assessment tool.
Heart and Brain: Heart rate variability links to cognition?
The autonomic nervous system consists of two subsystems: flight and fight activity (sympathetic drive) and rest and digest activity (parasympathetic drive). Heart rate variability (HRV) is a non-invasive analysis of the interplay between these autonomic branches. Our research investigates the relationship between the autonomic nervous system measured by HRV and cognitive function. Specifically this project explores the potential use of HRV as an early biomarker for determining who is at risk for mild cognitive impairment. Mild cognitive impairment is an earlier stage that precedes dementia. Thus, early identification of mild cognitive impairment would facilitate the application of timely and preventative intervention measures to delay or prevent cognitive decline and ultimately dementia. The most common form of dementia, Alzheimer’s disease, is a progressive disease with no known cure, thus a focus on early detection and prevention is crucial.
Is the plasminogen system a link between head trauma and the increased risk of dementia?
Individuals who have sustained brain trauma have a 2-13.5 fold increased risk of developing Alzheimer disease (AD), Frontotemporal dementia, Lewy body dementia and Chronic Traumatic Encephalopathy or Dementia Pugilistica.
Plasminogen is an enzyme that is activated yield plasmin which degrades blood clots in the circulation. In the brain, plasmin facilitates the clearance of amyloid-beta plaques. Plasmin activity is reduced in the brains of AD patients, which may be the reason for the extensive accumulation of amyloid-beta. Accordingly, compounds that increase plasmin activity minimise amyloid-beta pathology in mice with AD. Plasminogen activation is also down-regulated in the presence of alpha-synuclein, a protein that accumulates in Lewy bodies, a pathological feature of Lewy Body Dementias.
Aggregation of proteins including amyloid-beta, alpha synuclein, Tau and TDP-43 are a pathological hallmark of the aforementioned dementias. We have shown that trauma rapidly induces protein aggregation in mice and humans, and these aggregates are not efficiently cleared in plasminogen deficient (plasminogen -/-) mice. Dr Sashindranath hypothesise that a reduction in plasmin activity causes increased aggregation of amyloid-β, alpha synuclein, Tau and TDP-43, which can accelerate dementia-related pathology after trauma. If so, compounds that increase plasmin activation in the brain may aid in preventing dementia after head trauma.
Access to dementia care and support services in rural Victorian communities
Ms Chisolms' research aims to explore and understand the experiences of people in rural Victorian communities with dementia and their carers when seeking to access care and support services, describing the pathways taken, barriers and facilitators to access, as well as the information needs of carers. Most importantly, her research aims to improve access to timely and appropriate services to meet both the needs of the person with dementia and their carer.
Improving the health and wellbeing of community dwelling carers of people with dementia - a randomised controlled trial of structured mediation training
The impact of dementia on family caregivers is substantial. In financial terms, carers may experience loss of earnings, either from reduced working hours or relinquished employment. Carers of people with dementia also report high levels of stress, social isolation, sleep disturbance, depression, anxiety and impaired cognitive performance, as well as reduced quality of life. Some complementary therapies, specifically relaxation therapies, have demonstrated promising effects in the management of a variety of stress-related conditions, including anxiety. The relaxation technique selected for this study, Transcendental Meditation® (TM), has been selected by the research team as having potential to reduce stress levels and improve the quality of life of dementia caregivers. Carers enrolled in the clinical trial will be randomly assigned to twelve weeks of TM training or group support. Participants will, in addition, be required to complete a series of short tests at the beginning and end of the trial, and twelve weeks after trial completion (follow-up). This will enable the researchers to better understand whether trained meditation practices can improve important outcomes relevant to dementia caregivers, including quality of life, mood, and the ability to process, understand and remember information.
Axonal transport defects in Alzheimer's disease and related disorders: mechanisms of tau pathology
Alzheimer’s disease (AD) is characterized by two types of insoluble protein deposits in the brain, tau-containing neurofibrillary tangles and β-amyloid (Aβ)-containing plaques. Although axonal transport has been proposed as a potential pathomechanism of tau, the precise sequence of the cellular events that underlie such tau-dependent transport defects are only poorly understood. Due to the complexity of real-time analysis of neuronal functions in intact behaving mouse models, most research into the role of tau in axonal transport involves the use of cultured cells. However, these experimental systems fail to reproduce the complex cellular and systemic influences that determine cellular functions in vivo. The roundworm C. elegans is, however, ideally suited for these purposes due to its transparency, short life cycle, concise neuroanatomy and well-characterized genetics. Here we propose to exploit the powerful genetic tools available in C. elegans, together with advanced real-time microscopy of fluorescently labelled proteins, to gain insights into the pathological mechanisms that cause tau to impair axonal transport. Understanding the pathogenic pathways and molecular components underlying the progressive axonal transport defects in tauopathies over time will provide a framework for the development of novel therapeutic strategies.
The modeling of presenilin (Alzheimer's disease) mutations in zebrafish embryos
To reduce the social and financial impacts of Alzheimer's disease, preventative treatments are needed. An increased understanding of Alzheimer's disease is essential for development of such treatments. Although there is still disagreement about what actually causes this disease, we do know that the majority of inherited cases of Alzheimer’s disease are caused by changes in the PRESENILIN genes. These genes are centrally important to the functioning of cells. However, we are only beginning to understand how PRESENILINs function. Like humans, zebrafish possess versions of the PRESENILIN genes. We use the very advantageous characteristics of zebrafish to investigate how PRESENILINs function. One aim of this project has been to investigate the function of shortened forms of the PRESENILIN protein. The results of our work so far suggest that these shortened forms may affect the way toxic debris is cleared from cells. For our second aim, we have generated mutant zebrafish that have changes in their PRESENILIN genes similar to what is seen in Alzheimer’s disease. These fish will be a very valuable resource for further research on the function of the PRESENILIN proteins in different cellular mechanisms implicated in Alzheimer’s Disease. Therefore, future research utilising these mutant fish will help us understand the mechanisms behind Alzheimer's Disease.
Improving pain management amongst people with dementia
People with dementia may have pain but unable to report it because of impaired cognition. Therefore, we have developed a mobile application to assist caregivers and family members identify pain in dementia patients who cannot communicate. The app is integrated in a smart phone which uses the built-in camera to perform automated facial recognition together with certain pain indicators. To our knowledge this is a world’s first electronic pain assessment tool for dementia patients that utilises automated facial recognition technology and mobile platform with the view of reducing user subjectivity and hence more accurately detect pain. The next phase of this project is testing in human subjects and hence validating the electronic pain assessment tool.
The pathway linking the tau and amyloid precursor proteins in neurodegeneration
Lithium is first-line therapy for bipolar disorder, but has many side effects that limit its use. One side effect is parkinsonism. Understanding the molecular mechanism of lithium-induced parkinsonism is of importance for bipolar disease, but will also contribute to our understanding of Parkinson’s disease. He has previously found that a protein called ‘tau’ is reduced in the brains of Parkinson’s disease patients, and reducing tau in mice recapitulated a number of key symptoms of Parkinson’s disease. He has been able to demonstrate that tau reduction caused iron accumulation in mouse brain, which manifested symptoms of Parkinson’s disease. In this project, we showed that lithium treatment to cells caused tau-mediated iron accumulation, and lithium treatment to normal mice (at the therapeutic dose) caused parkinsonism via tau mediated pathway. He further analysed brain-iron content (by MRI) in a group of healthy volunteers before and after they took lithium, and found iron elevation in a region of the brain associated with Parkinson’s disease. These results are in accordance with his previous findings that collectively support the direct involvement of tau protein in Parkinson’s disease in addition to its unique role in Alzheimer’s disease.
Quantification of vascular damage and mircobleeds using susceptibility weighted imaging with application to normal ageing and Alzheimer's disease
Brain connectivity biomarkers predict specific memory consolidation deficits across dementia subtypes
Mr Tu's research investigates different aspects of memory in dementia sufferers and how changes to a series of brain structures that comprise the ‘limbic memory circuit’ can affect their performance in the early stages of the disease. Moving away from the traditional approach of looking solely at the hippocampus, he looks at multiple interconnected brain structures that are all involved in memory processes. Over the past year he has successfully reconstructed a critical white matter pathway using neuroimaging techniques to allow investigation of the memory circuit, and whether he can detect changes that will aid diagnosis in the earliest stages of dementia.
Another aspect of my project is developing novel clinical tests that can improve classification of dementia into its subtypes, in particular Alzheimer’s disease and behavioural variant frontotemporal dementia. Two mental processes that show distinct changes in these conditions are long-term memory and orientation. He has now developed an online test of long-term memory as well as a realistic virtual assessment of orientation that are currently being piloted in patients.
Neuroimaging in early detection of Alzheimer's disease with ADNI
Neuroimaging plays an essential role in human clinical neuroscience. As imaging technology advances, the large-scale high-quality data could provide important insights of the pathology of neurological disorders, such as Alzheimer's disease. In this project, I aim to analyze the neuroimaging data and integrate the findings into computer aided diagnosis pipelines for Alzheimer's disease and mild cognitive impairment (MCI). The main objective of this project is to identify the early signs of cognitive impairment, thus keep contributing to the long-term objective, which is to deliver integrated and patient-centered healthcare to individuals with Alzheimer's disease or MCI.