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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Caress the Detail: A Comprehensive MRI Atlas of the in Vivo Human Brain

This project aims to deliver the most comprehensive, detailed and stereotaxically accurate MRI atlas of the canonical human brain. In human neuroscience, researchers and clinicians almost always investigate images obtained from living individuals. Yet, there is no satisfactory MRI atlas of the human brain in vivo or post-mortem. There are some population-based atlases, which valiantly solve a number of problems, but they fail to address major needs. Most problematically, they segment only a small number of brain structures, typically about 50, and they are of limited value for the interpretation of a single subject/patient. In contrast to population-based approaches, the present project will investigate normal, living subjects in detail. We aim to define approximately 800 structures, as in the histological atlas of Mai, Majtanik and Paxinos (2016), and, thus, provide a “gold standard” for science and clinical practice. We will do this by obtaining high-resolution MRI at 3T and 7T of twelve subjects through a collaboration with Markus Barth from the Centre for Advanced Imaging at the University of Queensland (UQ). The limited number of subjects will allow us to image each for longer periods, obtaining higher resolution and contrast, and to invest the required time to produce unprecedented detail in segmentation. We will produce an electronic atlas for interpreting MR images, both as a tablet application and as an online web service. The tablet application will provide a convenient and powerful exegesis of brain anatomy for researchers and clinicians. The open access web service will additionally provide images, segmentation and anatomical templates to be used with most common MR-analysis packages (e.g., SPM, FSL, MINC, BrainVoyager). This will be hosted in collaboration with UQ, supporting and complementing their population-based atlas.
PROJECT