Digitally created image of brain in skull

ForeFront

RESEARCH CENTRE

Our laboratory research

At disease onset, focal pathology restricted to distinct brain areas is a feature of FTD and MND. However, the disease progresses and spreads by unknown mechanisms and the pattern of spread over time is poorly documented.

ForeFront will examine how progression occurs in the different clinical syndromes and proteinopathies using three main branches of laboratory-based research.

1. Human brain pathology – Prof Glenda Halliday and Prof Jillian Kril

Prof Halliday coordinated the first clinicopathological and survival studies published on frontotemporal disease and her laboratory developed the tool now used internationally to stage the disease. Prof Kril developed postmortem volumetric techniques, and is recognised for her quantitative studies on these and other neurodegenerative conditions. Their data are been used in all the pathological criteria for these diseases.

Key area of research for the first year:

Retrospective clinical analyses (Halliday and Hodges) – Postmortem cases will be stratified according to clinical syndromes and a range of defined candidate cognitive, linguistic, behavioural and radiological features assessed using multivariate statistics.

Retrospective pathological analyses (Kril) – We will apply a full range to immunohistological stains to the large clinically well-documented cohort of postmortem patients with particular clinical syndromes and multivariate statistics applied to identify features predictive of the underlying pathology.

2. Cellular and molecular studies – Assoc Prof Lars Ittner

Assoc Prof Ittner recently identified the mechanism of interaction between tau and Abeta, and has recently published cell TDP models using his new neuronal culture system.

Key area of research for the first year:
Molecular mechanisms of toxicity – A wide range of molecular mechanisms and pathways will be studied in primary cell culture to determine the contribution to cell death induced by different species (e.g. those identified above as contributing to progression) and mutant forms of tau, TDP43 and FUS. The protein-specific toxicity profiles will be compared to establish a complex network of shared and distinct modes of pathogenic pathways.

identification of vulnerability genes by forward genetics
3. Animal modelling – Prof Jürgen Götz

Prof Götz, who developed the first transgenic mouse model of frontotemporal disease, has continued to develop animal models and other tools to look at a variety of disease mechanisms.

Key area of research for the first year:

Identifying genes that confer protection – To identify protective genes, Affymetrix gene chips and differential gene expression will be used for transcriptional profiling of laser-captured dopamine neurons from K3 mice and non-transgenic controls, and validated with quantitative RT-PCR. We expect to identify several hundred candidate genes differentially expressed in dopamine neurons, a small subset of which will confer protection to tau-mediated neurodegeneration. To determine whether the ‘persisting’ genes confer ‘survival’, we will use in situ hybridisation and immunohistochemistry to analyse brain sections of a wide age range of K3 and non-transgenic control mice to determine which genes discriminate vulnerable from protected neurons.

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Abdominal muscle stimulation to improve bowel function in spinal cord injury

Bowel complications, resulting from impaired bowel function, are common for people living with a spinal cord injury (SCI). As a result, people with a SCI have high rates of bowel related illness, even compared with those with other neurological disorders. This includes high rates of abdominal pain, constipation, faecal incontinence and bloating. These problems lower the quality of life of people with a SCI and place a financial burden on the health system. A treatment that improves bowel function for people with a SCI should reduce illness, improve quality of life and lead to a large cost saving for health care providers. Bowel problems have traditionally been managed with manual and pharmacological interventions, such as digital rectal stimulation, enemas, and suppositories. These solutions are usually only partially effective, highlighting the need for improved interventions. The abdominal muscles are one of the major muscle groups used during defecation. Training the abdominal muscles should improve bowel function by increasing abdominal pressure. During our previous Abdominal FES research with people with a SCI, we observed that Abdominal FES appeared to lead to more consistent and effective bowel motion. However, this evidence remains anecdotal. As such, we are going to undertake a large randomised controlled trial to investigate the effectiveness of Abdominal FES to improve the bowel function of people with a SCI. This study will make use of a novel measurement system (SmartPill, Medtronic) that can be swallowed to measure whole gut and colonic transit time. We will also assess whether Abdominal FES can change constipation-related quality of life and the use of laxatives and manual procedures, as well as the frequency of defecation and the time taken. A positive outcome from this study is likely to lead to the rapid clinical translation of this technology for people living with a SCI.
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