Cognition In Cerebellar Degeneration: Correlations With Lateral Neocerebellar Dysfunction And Atrophy
Funder
National Health and Medical Research Council
Funding Amount
$205,500.00
Summary
Diseases of the main brain coordination centre (the cerebellum) were once thought to impair only movement skills. However, effects on thinking, and especially on mental flexibility and rational planning, are increasingly being reported. These cognitive difficulties may hinder rehabilitation. They also often cause tension within the sufferers' families if other family members are not aware that such difficulties are part of the disease and beyond the sufferers' control. We will test how common su ....Diseases of the main brain coordination centre (the cerebellum) were once thought to impair only movement skills. However, effects on thinking, and especially on mental flexibility and rational planning, are increasingly being reported. These cognitive difficulties may hinder rehabilitation. They also often cause tension within the sufferers' families if other family members are not aware that such difficulties are part of the disease and beyond the sufferers' control. We will test how common such thinking difficulties are in patients with different inherited forms of incoordination, and determine what aspects of thinking are particularly affected. We will see whether the severity of movement incoordination predicts the extent of thinking disruption, as different but neighbouring parts of the cerebellum seem to be involved in each. We will also use magnetic brain scans (MRI's) to check that the thinking problems are not caused by shrinkage of other parts of the brain in these diseases.Read moreRead less
ATM Activation And Its Functional Importance In DNA Damage Response
Funder
National Health and Medical Research Council
Funding Amount
$555,541.00
Summary
ATM is the protein deficient in the human genetic disorder ataxia-telangiectasia (A-T). This syndrome is characterised by neurodegeneration and increased risk of cancer. ATM recognises damage in DNA and facilitates its repair to minimize the risk of genetic defects. The project is designed to investigate the mechanism of activation of ATM. This information is important to understand the role of ATM in preventing cancer.
Characterisation Of Neuregulin-2 Function In The Nervous System.
Funder
National Health and Medical Research Council
Funding Amount
$183,250.00
Summary
The Neuregulins (NRG's) are a family of four structurally related growth factors expressed in the developing and adult brain. NRG-1 is essential for life and has been implicated in the development and maintenance of both neurons and glial cells, as well as being essential for normal heart formation. NRG-2 was identified by us and others as being closely related to NRG-1 and, like NRG-1, it is also expressed predominantly in neuronal populations of the brain. One striking feature of NRG-2 express ....The Neuregulins (NRG's) are a family of four structurally related growth factors expressed in the developing and adult brain. NRG-1 is essential for life and has been implicated in the development and maintenance of both neurons and glial cells, as well as being essential for normal heart formation. NRG-2 was identified by us and others as being closely related to NRG-1 and, like NRG-1, it is also expressed predominantly in neuronal populations of the brain. One striking feature of NRG-2 expression in the adult brain is its localisation to regions associated with neurogenesis (renewal of neurons from stem cell precursors). Outside the nervous system Neuregulin-2 can stimulate the proliferation and differentiation of epithelial cells. However, little is known about the activity of Neuregulin-2 in the brain. This grant proposal aims to study the biological functions of Neuregulin-2 in the developing and adult central nervous system. The experimental design is based on characterisation of mice that do not contain the Neuregulin-2 gene. We will also look specifically at the action of Neuregulin-2 on discrete populations of neuronal cells, grown in tissue culture. We expect that these studies will provide valuable insight into the role of NRG-2 in the brain and that they will be the basis for defining the mechanisms by which NRG-2 activity differs to that of the NRG family members. By studying factors that are involved in the development of the nervous system it is hoped that valuable insights will be made regarding repair and regeneration in the adult brain.Read moreRead less
Bipolar affective disorder (BP), or manic-depressive illness, is a major cause of disability and mortality worldwide. It has a lifetime prevalence of about 1% and suicide risk of about 20%. The disorder is characterised by episodes of mania or hypomania and depression, appearing in varying succession, with or without intermission. Twin, family, and adoptive studies point to a strong genetic component leading to the development of bipolar disorder, with a heritability of the order of 80%. Yet the ....Bipolar affective disorder (BP), or manic-depressive illness, is a major cause of disability and mortality worldwide. It has a lifetime prevalence of about 1% and suicide risk of about 20%. The disorder is characterised by episodes of mania or hypomania and depression, appearing in varying succession, with or without intermission. Twin, family, and adoptive studies point to a strong genetic component leading to the development of bipolar disorder, with a heritability of the order of 80%. Yet the identification of the genetic basis of the disease has proved exceedingly difficult, with numerous studies producing no definitive data. The lack of convincing results has been interpreted as an indication of complex genetic mechanisms and underlying differences between affected families and ethnic groups. Genetically isolated populations, where most individuals descend from a small number of founders, are believed to hold great potential for understanding the genetic basis of complex diseases, such as bipolar disorder. Affected subjects in such populations are likely to share the same predisposing genes, making these genes easier to identify. During the last 10 years, we have been involved in the study of bipolar disorder in one such population, with very promising results. In this project, we propose to take the research further by collecting more affected families, confirming the current positive findings and narrowing down the search to a small region, possibly a single gene. If successful, the study will be a major breakthrough which, by identifying a molecular pathway and disease mechanism, will contribute valuable and generally valid information on the biological basis of mood disorders.Read moreRead less
Understanding The Role Of Muscarinic Receptors In The Pathophysiology Of Depression And Bipolar Disorder
Funder
National Health and Medical Research Council
Funding Amount
$480,074.00
Summary
The causes of bipolar disorder and major depressive disorder, which effect many Australians, remain unknown. We have recently shown decreases in muscarinic receptors in the brain of people with bipolar disorder and major depressive disorder. Muscarinic receptors are important in maintaining the functions of the brain that seem to be affected in people with bipolar disorder and major depressive disorder. Here we seek to understand how changes in muscarinic receptors occur in both disorders.
Anti-Estrogens - A Potential Treatment For Bipolar Affective Disorder In Women?
Funder
National Health and Medical Research Council
Funding Amount
$239,250.00
Summary
Bipolar Affective Disorder (BPAD) or Manic-Depressive Illness is a serious mental illness with high morbidity and mortality. The cause of the illness is still unclear and the underlying neurochemical changes are different for the manic phase compared with the depressive phase. The current treatments for BPAD are limited in scope and not biochemically well understood. There are gender differences in the presentation and outcomes for BPAD which adds to the complexity of the illness. We are proposi ....Bipolar Affective Disorder (BPAD) or Manic-Depressive Illness is a serious mental illness with high morbidity and mortality. The cause of the illness is still unclear and the underlying neurochemical changes are different for the manic phase compared with the depressive phase. The current treatments for BPAD are limited in scope and not biochemically well understood. There are gender differences in the presentation and outcomes for BPAD which adds to the complexity of the illness. We are proposing a study to develop a new type of treatment for the manic phase of BPAD and are exploring the use of anti-estrogens in women with mania. The background to our proposed study comes from a few case reports suggesting that anti-estrogen agents such as progesterone and tamoxifen may be useful adjuncts to treatment. We conducted a small pilot study comparing the addition of oral tamoxifen with oral progesterone and placebo in 10 women with mania and found that the women who received tamoxifen made significantly better improvements in their manic symptoms over a 28-day trial. The research study we are now proposing is a larger, three-arm, double blind, placebo controlled, 28-day adjunctive study in women with mania to expand and clarify our pilot study findings. Patients in our proposed study would receive either 40mg per day tamoxifen or 20mg per day progesterone or placebo in addition to standardised lithium medication. We will measure enzyme activity (protein kinase C) and estrogen-progesterone levels to understand more about the mechanisms of action by these new hormone treatments. BPAD is a crippling disorder and if we are successful, then tamoxifen treatment may be an important new treatment. This proposed study will also shed new light on some of the neurochemical mechanisms underlying BPAD as well as opening up the new area of hormone treatments for serious mental illness.Read moreRead less
High-Throughput Screening Of The Genome And Proteome In Postmortem CNS From Subjects With Schizophrenia
Funder
National Health and Medical Research Council
Funding Amount
$553,190.00
Summary
Schizophrenia is a serious psychiatric illness that effects ~1% of the Australia population. The underlying pathology of the illness remains unknown. This application seeks funding to use new technologies to screen approximately 60% of the expressed human genome and proteome to determine which genes are being differentially expressed in two regions thought to be important in generating the symptoms of the illness, the frontal cortex and hippocampus. This project will generate a large amount of d ....Schizophrenia is a serious psychiatric illness that effects ~1% of the Australia population. The underlying pathology of the illness remains unknown. This application seeks funding to use new technologies to screen approximately 60% of the expressed human genome and proteome to determine which genes are being differentially expressed in two regions thought to be important in generating the symptoms of the illness, the frontal cortex and hippocampus. This project will generate a large amount of data, however by comparing the data from subjects with schizophrenia to that from control subjects and subjects with bipolar disorder who were psychotic and being treated with antipsychotic drugs close to death will allow us to identify changes that are specific to schizophrenia. Genes that are expressing different levels of mRNA and protein will become prime targets for future investigations as they are likely to be central to the pathology of the illness.Read moreRead less
A Double-blind Placebo Controlled Trial Of Transcranial Magnetic Stimulation In The Treatment Of Depression.
Funder
National Health and Medical Research Council
Funding Amount
$366,775.00
Summary
Depression is a severe and often disabling illness that occurs frequently in the general population. Depression is a treatable illness and the majority of patients will respond to anti-depressant medication, a form of psychotherapy or a combination of these. However, a significant percentage of patients with depression fail to respond to these therapies and currently require electroconvulsive therapy (ECT). This entails the complications and costs of multiple anaesthetics, memory impairment and ....Depression is a severe and often disabling illness that occurs frequently in the general population. Depression is a treatable illness and the majority of patients will respond to anti-depressant medication, a form of psychotherapy or a combination of these. However, a significant percentage of patients with depression fail to respond to these therapies and currently require electroconvulsive therapy (ECT). This entails the complications and costs of multiple anaesthetics, memory impairment and substantial social stigma. Transcranial magnetic stimulation is being researched as a potential alternative for these patients. It is administered to patients who are awake and alert and appears to have fewer side effects. TMS uses the unique properties of a magnetic field to produce or disrupt electrical activity in superficial areas of the brain, targeted to the areas thought to be involved in the cause of depression. Our research study will compare the two most promising types of TMS with an inactive or placebo condition. This is important to establish that the effects of TMS arise from the actual stimulation and to investigate whether one of two types of TMS administered is superior. We will administer this treatment for between 2 and 4 weeks and assess the response. We anticipate that our research will contribute to the development of TMS as a treatment methodology for this important patient group. It is crucial that a new treatment be thoroughly evaluated prior to wide dissemination of it in clinical practice. We will help define the effectiveness of this treatment and the most appropriate way in which it can be administered.Read moreRead less