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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Brain and Knee Muscle Weakness Study

Why Does Quadriceps Weakness Persist after Total Knee Replacement? An Exploration of Neurophysiological Mechanisms Total knee replacement is a commonly performed surgery for treating end-staged knee osteoarthritis. Although most people recover well after surgery, weakness of the quadriceps muscles (the front thigh muscles) persists long after the surgery (at least for 12 months), despite intensive physiotherapy and exercise. Quadriceps muscle weakness is known to be associated with more severe pain and greatly affect daily activities. This study aims to investigate the mechanisms underlying weakness of the quadriceps muscles in people with knee osteoarthritis and total knee replacement. We hope to better understand the relationship between the changes of the brain and a loss of quadriceps muscle strength after total knee replacement. The study might be a good fit for you if you: Scheduled to undergo a total knee replacement; The surgery is scheduled within the next 4 weeks; Do not have a previous knee joint replacement in the same knee; Do not have high tibial osteotomy; Do not have neurological disorders, epilepsy, psychiatric conditions, other chronic pain conditions; Do not have metal implants in the skull; Do not have a loss of sensation in the limbs. If you decide to take part you would: Be contacted by the researcher to determine your eligibility for the study Be scheduled for testing if you are eligible and willing to take part in the study Sign the Consent Form when you attend the first testing session Attend 3 testing sessions (approximately 2 hours per session): 1) before total knee replacement, 2) 3 months and 3) 6 months after total knee replacement. The testing will include several non-invasive measures of brain representations of the quadriceps muscles, central pain mechanisms, and motor function and questionnaires. Will I be paid to take part in the research study? You will be reimbursed ($50.00 per session) for travel and parking expenses associated with the research study visits. If you would like more information or are interested in being part of the study, please contact: Name: Dr Wei-Ju Chang Email: w.chang@neura.edu.au Phone: 02 9399 1260 This research is being funded by the Physiotherapy Research Foundation.  
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