Finding Clinical Predictors For The Underlying Pathology In Different Frontotemporal Dementia (FTD) Syndromes
Funder
National Health and Medical Research Council
Funding Amount
$136,593.00
Summary
Due to the ageing population in Australia it is predicted that the prevalence of dementia will increase four-fold by 2050. Developing disease-modifying therapies for dementia is therefore a priority, however we also need to be able to accurately identify patients for whom these therapies will be beneficial. Here we will develop strategies for identifying patients with particular protein abnormalities in their brain, the substrate of most therapeutic interventions.
Blood Protein Biomarkers For Frontotemporal Lobar Degeneration
Funder
National Health and Medical Research Council
Funding Amount
$184,305.00
Summary
This project will assess blood proteins as biomarkers for different pathogenic forms of frontotemporal dementia (FTD), one of the major neurodegenerative dementias with a very rapid disease progression (mean survival 3 years). At present, it is not possible to predict which pathological variant is present in any given patient. We plan to develop blood protein biomarker assays capable of diagnosing the pathology in vivo.
PATHOGENESIS OF ALZHEIMERS DISEASE AND RELATED DISORDERS: MECHANISM OF TAU PATHOLOGY
Funder
National Health and Medical Research Council
Funding Amount
$295,983.00
Summary
A protein called tau has an essential role in the pathogenesis of Alzheimer's disease (AD), frontotemporal dementia (FTD) and related dementias. We have developed novel transgenic models, which allow us to treat the mice and to abrogate the clinical symptoms. As we have dissected the underlying molecular mechanisms, our ultimate goal is to develop a treatment approach based on these mechanisms and thereby reduce the socio-economic burden of these debilitating diseases.
Investigation Of Dysfunction Of SIGMAR1 In Transgenic Mouse Models, A Novel Gene Implicated In Neurodegeneration
Funder
National Health and Medical Research Council
Funding Amount
$492,119.00
Summary
At present, there are no effective therapies for frontotemporal dementia or motor neuron disease. We have identified the SIGMAR1 gene as having a crucial role for these diseases. More importantly, there are therapeutically relevant small molecule drugs that are known to modulate the activity of this gene. We aim to determine the efficacy of pharmacological modulation of Sigma-1 receptor activity in mouse models of dementia.
Pathogenic Mechanisms Common To All Subtypes Of Frontotemporal Dementia
Funder
National Health and Medical Research Council
Funding Amount
$511,294.00
Summary
Frontotemporal dementia (FTD) is a neurodegerative disease of unknown cause and without effective treatment. While there are a number of clinical and pathological subtypes of FTD all have abnormal protein deposition. In this project we will investigate using brain tissue from patients with FTD, transgenic mice and culture models the cellular mechanisms which underly the protein depsotion. In addition, we will look at the brain's response to injury and investigate modulation of this response.
Feeding Disturbance And Hypothalamus Integrity In Early Frontotemporal Dementia
Funder
National Health and Medical Research Council
Funding Amount
$428,319.00
Summary
Frontotemporal dementia accounts for 12-20% of all dementia cases. It is as common as Alzheimer�s disease in the < 65 year olds but understanding of this disease remains limited. Marked eating disturbance (overeating, snatching food) is a common clinical manifestation. This project will characterise this deficit and define its biological causes using blood tests and magnetic resonance imaging. Results will help in designing therapeutic interventions targeting this disabling feature.
Non-Alzheimer Dementia: Pathogenesis And Clinicopathological Correlations
Funder
National Health and Medical Research Council
Funding Amount
$437,036.00
Summary
Dementia affects as many as 20% of people in their eighties. Although much of this is caused by Alzheimer's disease (AD), other types of dementia are also important. In this study we will look at two types of non-Alzheimer dementia, frontotemporal dementia (FTD) and small vessel cerebrovascular disease (SVD). The clinical symptoms of SVD closely resemble AD. Conversely, FTD results in degeneration of those parts of the brain which are responsible for personality, behaviour and language. We will ....Dementia affects as many as 20% of people in their eighties. Although much of this is caused by Alzheimer's disease (AD), other types of dementia are also important. In this study we will look at two types of non-Alzheimer dementia, frontotemporal dementia (FTD) and small vessel cerebrovascular disease (SVD). The clinical symptoms of SVD closely resemble AD. Conversely, FTD results in degeneration of those parts of the brain which are responsible for personality, behaviour and language. We will look at the brains of patients who have died with these diseases and determine the types of neurons which are damaged and their distribution in the brain. We will also investigate whether an individual's genetic make-up influences the development of SVD. In addition, in collaboration with neuropathologists across Australia, we will develop and standardise criteria for the pathological diagnosis of these diseases. Overall, this study will better characterise the pathology of two commonly encountered non-AD dementias and provide valuable insights into their causes.Read moreRead less
Understanding The Variation In Frontotemporal Dementia
Funder
National Health and Medical Research Council
Funding Amount
$417,750.00
Summary
Frontotemporal dementia (FTD) is one of the non-Alzheimer dementias which accounts for between 12 and 20% of all dementia and as much as 50% of early onset dementia. It is characterised by marked behavioural change and thus patients with this disease present a major management challenge. The cause of FTD is unknown and at present there is no effective treatment for the disease. There are a number of different clinical subtypes of FTD, namely behavioural variant, language variant, and FTD with mo ....Frontotemporal dementia (FTD) is one of the non-Alzheimer dementias which accounts for between 12 and 20% of all dementia and as much as 50% of early onset dementia. It is characterised by marked behavioural change and thus patients with this disease present a major management challenge. The cause of FTD is unknown and at present there is no effective treatment for the disease. There are a number of different clinical subtypes of FTD, namely behavioural variant, language variant, and FTD with motor neuron disease (FTD+MND). Similarly there are pathological subtypes of FTD (Pick's disease, frontotemporal lobar degeneration and FTD with ubiquitin-positive MND inclusions). However, there appears to be little correspondence between these two subdivisions. The purpose of this study is to investigate the pathological differences and similarities between the different clinical subtypes of FTD. Furthermore, we will investigate the changes in brain atrophy which occur over the course of the disease to allow us to understand better the initial focus of the disease. We will also evaluate the role of cellular protein changes (ubiquitin and tau) in the pathogenesis of neuronal death. This research will allow us (i) to better diagnose and characterise FTD and (ii) establish any common mechanisms of neurodegeneration in the subtypes of FTD.Read moreRead less
Alzheimer's Disease And Related Disorders: Mechanism Of Tau Pathology In Established And Novel Transgenic Animal Models
Funder
National Health and Medical Research Council
Funding Amount
$423,017.00
Summary
Alzheimer's disease (AD) is a devastating neurodegenerative disease for which no cure is available. It affects more than 15 million people worldwide. There are estimates that by 2040, approximately 500'000 Australians will suffer from AD, with associated health costs of about 3% of the GDP. AD is characterized by two major brain lesions, beta-amyloid plaques and neurofibrillary tangles (NFTs). The latter contain a protein called tau which is in a fibrillar and highly phosphorylated state. We wer ....Alzheimer's disease (AD) is a devastating neurodegenerative disease for which no cure is available. It affects more than 15 million people worldwide. There are estimates that by 2040, approximately 500'000 Australians will suffer from AD, with associated health costs of about 3% of the GDP. AD is characterized by two major brain lesions, beta-amyloid plaques and neurofibrillary tangles (NFTs). The latter contain a protein called tau which is in a fibrillar and highly phosphorylated state. We were the first to establish a transgenic animal model of pre-tangles and, together with Dr. Hutton's laboratory, of NFT formation. We could further show that injections of beta-amyloid into brains of our tau mutant mice enhanced the NFT pathology in these mice. By Functional Genomics we identied genes and proteins, which are induced by tau expression. The specific aim of this proposal is to determine whether oxidative stress enhances the tau pathology in our tau mutant mice and whether distinct brain areas are particularly susceptible to this kind of stress. The reason for addressing this question is twofold: On the one hand, we have found in our mice that reactive oxygen species are increased, secondly it is known that some brain areas in the AD brain are degenerating, whereas others are not. A second aim is to develop novel tau transgenic models where individual interactions of tau with cellular proteins are disturbed. Finally, we want to determine whether the two kinases BMX and FAK and the phosphatase PPV regulate tau phosphorylation in vivo. Together, we hope that our efforts lead to a better understanding of the pathogenic mechanisms in AD and related disorders. As pathocascades are likely to be shared between a range of diseases, these findings may also contribute to other fields of research, such as Parkinson's disease. Ultimately, these efforts will assist in the development of a safe treatment of AD.Read moreRead less
What Contributes To Regional Vulnerability In Neurodegenerative Diseases? A Study Of Familial Cases.
Funder
National Health and Medical Research Council
Funding Amount
$456,655.00
Summary
Unfortunately, as many people live longer, more and more are afflicted by degenerative changes that affect their brain. These neurodegenerative diseases are usually relentlessly progressive and with time render patients incapable of many normal functions. For some families with certain genetic defects, these diseases occur aggressively and early. We would like to study the brains of patients from these families because in most cases the proteins affected by the gene defect have been identified. ....Unfortunately, as many people live longer, more and more are afflicted by degenerative changes that affect their brain. These neurodegenerative diseases are usually relentlessly progressive and with time render patients incapable of many normal functions. For some families with certain genetic defects, these diseases occur aggressively and early. We would like to study the brains of patients from these families because in most cases the proteins affected by the gene defect have been identified. However, despite knowing this important information, the reasons for the death of brain cells are still not understood. This project will provide important new information on which brain cells died in these patients and on the relationship between such cell death and any cellular protein changes. By comparing patients with different genetic defects we will be able to identify the main cellular mechanisms underlying these degenerative changes. This information is essential for the rational design of further experiments aimed at reducing the suffering of all patients with neurodegenerative diseases or at eliminating these diseases altogether.Read moreRead less