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.
Analgesic load, pain and daytime sedation in people with dementia in aged care facilities.
Alleviating suffering and maintaining quality of life are key objectives of providing care to people with dementia. However, people with dementia may experience and express pain indifferent ways to people without dementia. For this reasonpeople with dementia are typically prescribed less pain-relieving medicines than people without dementia. Pain expressed as behavioural symptoms is distressing for patients and carers. Behavioural symptoms may prompt clinicians to inappropriately prescribe psychotropic medicines (e.g. antipsychotics, hypnotic medicines). These medicines may be associated with adverse effects including excess sedation, falls and fractures, and an increased risk of death. Further research is needed to better understand the relationship between use of pain-relieving medicines, pain and daytime sedation. The results of this research will be used to produce geometric frameworks to provide patients, carers and clinicians with a visual representation of the association between use of pain-relieving medicines, pain and daytime sedation. This will provide valuable guidance and support to clinicians (e.g. general practitioners, nurses, pharmacists) who provide care to people with dementia.
The Watermemories Swimming Club
Care staff personal testimonials about participants involved in Watermemories Swimming Club exercise program for people with dementia report increased engagement, in addition to other positive behavioural and physical traits. However, while positive trends have emerged statistical analysis has not reflected the improvements reported. Project delivery shortcoming in recruitment and adherence are felt to be partially to blame for this. In addition, the feasibility of offsite delivery has also been questioned. Nevertheless, the program continues to grow in reputation as a novel and enjoyable approach to exercising adults with dementia in residential aged care.
Developing a blood test for the diagnosis of Alzheimer's disease
Dr Ryan's project is to study the blood of Alzheimer’s disease patients to find markers of the disease that we can use to develop a blood test for early detection of illness. Current methods for diagnosis are not very useful, as definitive diagnosis can only occur after death. His previous studies show that blood components can provide evidence of the disease, and, to enhance the accuracy of our current blood based indicators for Alzheimer’s disease, he is investigating changes in protein levels in the red blood cell fraction of blood. These cells have not been thoroughly investigated for general protein changes due to the large differences in the amount of various proteins present in the cells. The first part of his findings is the development of methods to remove the abundant proteins and be able to investigate the less abundant proteins. In doing this he has so far identified 20-40 proteins which have potential to act as diagnostic markers for the disease, and may form part of a blood test for Alzheimer’s disease in the future.
Controlling neuro-inflammation in Alzheimer's disease
By 2050 a million Australians are estimated to be diagnosed with Alzheimer’s disease, the most common neurodegenerative disorder worldwide. Current therapeutic strategies, although initially promising, have been ineffective in treating disease progression. The laboratory which Mr Minter is apart of focuses on neuro-inflammation, an aspect common to all Alzheimer’s sufferers but not yet targeted therapeutically. He has identified a critical novel regulator of this neuro-inflammation termed the type-1 interferons and we are investigating how they contribute to Alzheimer’s disease progression. He has detected significant elevations of type-1 interferon in human brains from patients who have died from Alzheimer’s disease and also in animal models of Alzheimer’s disease. In cell culture, neurons that have no type-1 interferon are protected against amyloid-beta, a key toxic protein which triggers neuronal death in Alzheimer’s disease. Other cells in the brain, termed glial cells, are also key players in neuro-inflammation. In healthy people these cells help keep neurons functioning and remove any unwanted or damaged tissue from the brain. In Alzheimer’s disease these cells can become hyper-active and damage healthy neurons, worsening disease progression. He has identified that type-1 interferons are important in controlling these events in glial cell culture and are currently investigating this finding further. He proposes that therapeutic targeting of neuro-inflammation in Alzheimer’s disease remains an unrecognised means of combating disease progression. Specifically, therapeutics targeting type-1 interferons or other related mediators may prove beneficial in treating the neurodegenerative disorder.