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Gene-environment Interaction In Healthy Brain Ageing And Age Related Neurodegeneration
Funder
National Health and Medical Research Council
Funding Amount
$2,162,805.00
Summary
Healthy ageing is characterised by low level of disability, high cognitive and functional capacity, and an active engagement in life. The most important ingredient of healthy ageing is a healthy brain, bereft of age-related diseases and dysfunction. Brain ageing and brain diseases are determined by multiple genetic factors that interact with environmental influences. The genes are multiple, the majority of which have a small influence. This study is an attempt to identify some of these genes and ....Healthy ageing is characterised by low level of disability, high cognitive and functional capacity, and an active engagement in life. The most important ingredient of healthy ageing is a healthy brain, bereft of age-related diseases and dysfunction. Brain ageing and brain diseases are determined by multiple genetic factors that interact with environmental influences. The genes are multiple, the majority of which have a small influence. This study is an attempt to identify some of these genes and investigate their interactions with environmental factors. It will use a unique resource, the NHMRC Australian Twin Registry (ATR) to identify elderly twins, and will also include the siblings of these twins so as to increase the ability to identify the important factors. The participants, who are listed on the ATR and recruited from NSW, Queensland and Victoria, will receive detailed neurological, psychiatric and cognitive assessments, and will undergo brain MRI scans. Their blood samples will be used to measure key chemicals that may affect brain ageing and to extract DNA for genetic tests. They will be followed-up every two years thereafter, and changes in their brain structure and cognitive functioning will be examined. Available statistical models will be used to examine gene-environment interactions and specific genes will be explored for their contribution to the additive genetic effects. This study will yield an important resource for national and international collaborations and has the potential to discover new genes.Read moreRead less
Characterization Ol A Novel Covalently Cross -linked Abeta Peptide Dimer And Its Role In Alzheimers Disease.
Funder
National Health and Medical Research Council
Funding Amount
$553,236.00
Summary
Currently there are limited therapeutic treatments and no cure for Alzheimer's disease (AD). The key protein causing AD is called Abeta. Abeta peptides form dityrosine cross-linked dimers (when 2 peptides join together) and this is thought to be responsible for killing brain cells in AD. Therefore, this proposal will determine the role of Abeta dimers in relation to killing brain cells and the progression of AD through analysis of their biological and biochemical properties.
Diabetes And Dementia: Studies With The Fremantle Diabetes Study Cohort.
Funder
National Health and Medical Research Council
Funding Amount
$315,509.00
Summary
Dementia is an extremely serious condition which affects a large proportion of the older population. Recent evidence has shown that diabetes, which is another common condition in the elderly, doubles the risk of an older person developing Alzheimer's disease and other forms of dementia. Why this happens is unknown but insulin therapy has been highlighted as a possible cause. As many older people are on insulin for their diabetes, it is extremely important to confirm or refute this finding. It se ....Dementia is an extremely serious condition which affects a large proportion of the older population. Recent evidence has shown that diabetes, which is another common condition in the elderly, doubles the risk of an older person developing Alzheimer's disease and other forms of dementia. Why this happens is unknown but insulin therapy has been highlighted as a possible cause. As many older people are on insulin for their diabetes, it is extremely important to confirm or refute this finding. It seems possible that insulin may not be the direct cause but that some other associated factor such as poor diabetes control, recurrent hypoglycaemic attacks or cerebrovascular disease causes dementia. On theoretical grounds, Alzheimer's disease may have a vascular basis. If Alzheimer's disease was, in part, caused by vascular disease then there is the potential to prevent cases of dementia developing by paying attention to the known risk factors for vascular disease such as hypertension. The Fremantle Diabetes Study is an ideal group of community living diabetic individuals in which we can study whether some or all of these factors cause Alzheimer's disease or dementia and gain insights into the potential for prevention.Read moreRead less
Amyloid Abeta In The Natural History Of Alzheimer's Disease
Funder
National Health and Medical Research Council
Funding Amount
$220,475.00
Summary
This grant is the continuation of a large series of experiments designed to uncover the basic causes of Alzheimer's disease. The focus is on closing some of the gaps in our knowledge of the natural history of Alzheimer's disease in relation to the deposition of the Abeta amyloid protein in the brain, which we believe plays a central role in the degeneration of nerve cells in this condition. The main questions we are tackling include: the feasibility of using assays of Abeta in the blood as a bio ....This grant is the continuation of a large series of experiments designed to uncover the basic causes of Alzheimer's disease. The focus is on closing some of the gaps in our knowledge of the natural history of Alzheimer's disease in relation to the deposition of the Abeta amyloid protein in the brain, which we believe plays a central role in the degeneration of nerve cells in this condition. The main questions we are tackling include: the feasibility of using assays of Abeta in the blood as a biological marker of Alzheimer's disease; whether better transgenic mouse models of Alzheimer's disease are required; whether the soluble forms of Abeta amyloid are the major species which cause neurotoxicity (in contrast to the insoluble forms which constitute the bulk of this protein in the Alzheimer's disease brain); and whether the intracellular or extracellular pathways of Abeta aggregation and toxicity are the key to understanding this disease. Increasing evidence suggests that the clearance of soluble forms of the Abeta protein from the brain may be a major therapeutic strategy. We therefore require further investigations of how these soluble forms of Abeta are generated in nerve cells, and how these forms exist in equilibrium with soluble and insoluble pools in the brain, cerebrospinal fluid, blood and other tissues of the body.Read moreRead less
The Modulation Of Metals To Improve The Cognitive And Pathological Features Of Alzheimers Disease
Funder
National Health and Medical Research Council
Funding Amount
$436,238.00
Summary
This proposal will characterise the effects of a novel therapy for the treatment of Alzheimer's disease. Our preliminary data show that this approach can affect both the onset and progression of the disease, as well as the symptoms that characterise it. Thus, a thorough assessment of these effects and this drug target provides a tangible movement towards a truly effective treatment for Alzheimer's disease.
The Physiological And Pathophysiological Roles Of Melanotransferrin
Funder
National Health and Medical Research Council
Funding Amount
$227,485.00
Summary
Melanotransferrin (MTf) is a membrane bound molecule that was originally identified in the malignant melanoma skin cancer and other tumours. Interestingly, MTf has many similarities to the serum iron-binding protein, transferrin, and initially MTf was thought to play a role in iron uptake by these cells. However, a series of studies by the applicant demonstrated that MTf did not play a major role in iron uptake by melanoma cells (Richardson et al. 1990, 1991a,b). In fact, most iron taken up by t ....Melanotransferrin (MTf) is a membrane bound molecule that was originally identified in the malignant melanoma skin cancer and other tumours. Interestingly, MTf has many similarities to the serum iron-binding protein, transferrin, and initially MTf was thought to play a role in iron uptake by these cells. However, a series of studies by the applicant demonstrated that MTf did not play a major role in iron uptake by melanoma cells (Richardson et al. 1990, 1991a,b). In fact, most iron taken up by these cells was via the binding of transferrin to the transferrin receptor. More recently, under the current NHMRC grant, we have been able to confirm and signficantly extend our previous studies to convincingly show that MTf is not involved in iron uptake by melanoma cells where it is expressed at very high levels (Richardson 2000 Eur. J. Biochem. 267 (in press). In addition, we showed that the expression of MTf in 50 human tissues was very different to transferrin and the transferrin receptor (TfR) that are well known to be involved in iron transport. For example, the TfR is expressed at high levels in tissues that require large amounts of iron eg. the placenta and bone marrow. In contrast, MTf was not expressed at high levels in these tissues, but was found in large amounts in unexpected locations such as the salivary gland. Furthermore, the expression of MTf was widespread through a variety of tissues, and in contrast to expectations, was found at higher levels in normal rather than fetal tissues. It is also intesting that MTf is found in the blood and brain of Alzheimer's disease patients. Our results suggest that MTf may play other unexpected roles apart from iron uptake. The present proposal will assess the roles of MTf in cellular functioning. This information will be very important in understanding the function of MTf in cancer cells, Alzheimer's disease and also in other tissues (eg. the salivary gland) where it is expressed at very high levels.Read moreRead less
The Mechanism, Predictive Value And Impact Of Apathy In Patients With Alzheimers Disease And Their Caregivers
Funder
National Health and Medical Research Council
Funding Amount
$542,370.00
Summary
Behavioural and psychological symptoms of dementia have been consistently associated with increased patients’ distress, and are considered by caregivers as the most difficult symptoms to manage. Apathy is the state of loss of motivation and emotional withdrawal that occurs in a high proportion of patients with Alzheimer’s disease. These patients require more management and support, given their reliance on others to schedule their activities and initiate behaviours even when they are still capabl ....Behavioural and psychological symptoms of dementia have been consistently associated with increased patients’ distress, and are considered by caregivers as the most difficult symptoms to manage. Apathy is the state of loss of motivation and emotional withdrawal that occurs in a high proportion of patients with Alzheimer’s disease. These patients require more management and support, given their reliance on others to schedule their activities and initiate behaviours even when they are still capable of performing the activities. In spite of the high frequency of apathy in dementia and the high potential of negative effects on patients and caregivers, little is known about the cause of this phenomenon, its potential influence upon the long-term progression of Alzheimer’s disease, and on its impact upon caregivers’ emotional well-being. The main aim of our proposal is to examine the mechanism, clinical relevance and impact of apathy in Alzheimer’s disease. More specifically, we will determine whether apathy predicts more severe depression, increasing motor problems, and a faster progression of cognitive and functional problems. Using state-of-the-art neuroimaging techniques we will examine the association between apathy and abnormalities in specific brain regions. Finally, we will examine whether caregivers of patients with apathy have relatively more severe emotional problems, a higher care giving burden and poor quality of life.Read moreRead less
A Multicentre Randomised Clinical Trial Of Physical Activity For The Treatment Of Patients With Alzheimers Disease
Funder
National Health and Medical Research Council
Funding Amount
$773,752.00
Summary
The number of older adults living with Alzheimer's disease (AD) will increase from 26.6 million to 106.2 million by 2050. In the absence of curative treatment options it is important to focus on non-pharmacological interventions such as physical activity. We propose to investigate whether a home-based physical activity program of 24 weeks for patients with AD can successfully decrease the rate of cognitive and functional declince and improve quality of life and psychological well-being.