Project - Towards treatments for non-Alzheimer neurodegenerative diseases by establishing their biology at all disease stages

All Chief investigators and associate investigators

Glenda Halliday

Research Project Abstract

Vision – To advance basic knowledge, develop diagnostic markers and identify treatment targets for the different molecular pathologies underlying non-Alzheimer neurodegenerative diseases at different stages (preclinical, with mild impairments, following disease conversion).

Synopsis – Neurodegenerative diseases are one of the most prevalent and growing causes of mortality and morbidity in Australia (4). They are currently classified in three overlapping ways, according to clinical syndromes (e.g. dementia, parkinsonism, motor neuron disease or MND), or anatomical distribution of degeneration (e.g. frontotemporal degenerations, extrapyramidal disorders, spinocerebellar degenerations), or by molecular abnormality (most common are amyloidoses, tauopathies, a-synucleinopathies, TDP-43 proteinopathies)(5), with a clear biological definition necessary for treatment purposes (1). While Alzheimer’s disease (AD, an amyloidosis and tauopathy that causes early memory impairment due to temporal lobe degeneration) is the most prevalent of these diseases in those aged >70y, under the age of 70y non-AD neurodegenerative diseases are as prevalent (6) but underrecognized (crucial early diagnosis non-existent) and more burdensome due to their more rapid functional lethality (7). In addition, pathological epidemiology shows that multiple neurodegenerative diseases are the norm in AD affected individuals (8-11), particularly with increasing age where the impact of coexisting non-AD pathologies in AD rises significantly accelerating disease severity and diminishing quality of life (12). No mechanistic treatments are available, and the inevitable coexistence of diverse molecular neurodegenerations in those >80y has implications for their accurate diagnosis and the development of mechanistic treatments (8-11).

My research aims to determine the impact of these non-AD molecular pathologies, and I will continue to increase biological knowledge of these diseases, focusing on their early biomarker diagnosis. To identify biomarkers, serial samples of peripheral tissues (eg. blood, skin, saliva) will be examined in known pre-symptomatic and mildly affected prodrome cohorts with genetic or clinical risk factors that identify the abnormal tau, a-synuclein and TDP-43. Similar biological samples in those meeting clinical criteria for disease, or controls without disease, will also be assessed following validation of any underlying molecular changes in their brain (collected with consent after death). Brain tissue will also be used to determine targetable cellular factors (particularly RNAs and pathological protein 'strains') in all types of brain regions (severely, mildly, non-affected) in each individual with disease and compared to controls. This will identify the earliest as well as later pathobiological changes for the known different molecular subtypes (4 for tau, 3 for a-synuclein, 4 for TDP-43). Different types of cells from blood and skin will be used to determine if there are any easily-accessible peripheral cells with similar subtype changes. Unbaised 'omic' analyses of fluids and tissue homogenates will determine targetable biomarkers that differentiate these diseases from each other and AD (found in 25% of those diagnosed with non-AD neurodegeneration). This research program will develop new early preclinical diagnostic tools and methods for identifying the underlying pathobiology of these diseases, and any targetable RNA dysfunction that develops and progresses (currently unknown).

Disease area:

Non-AD dementias

Project - Frontotemporal dementia and motor neurodegenerative syndromes

All Chief investigators and associate investigators

Glenda Halliday, John Mattick, John Hodges, Olivier Piguet, Jillian Kril, Lars Itnner, Michael Kassiou

Research Project Abstract

Over the last three years we have successfully established a cohesive research team, ForeFront, to spearhead research on frontotemporal dementia and motor neurodegenerative syndromes. These are a group of disorders with distinct clinical signs and symptoms and/or specific pathologies. They are rapidly progressive (average survival 1-3 years), cause behavioural, language or motor deficits (often in combination), and together are a leading cause of dementia, particularly in people aged <65 years. As ForeFront we developed a network of research clinics concentrating on these disorders that allowed the first treatment trials of these syndromes in Australia, determined clinical, imaging and biological markers of disease progression and specific neuropathologies, developed new authentic animal models that can now inform preclinical treatment trials, and partnered with international research teams to drive advances in diagnosis and management.

In addition, we identified a significant number of families with unusual genetic traits that warrant further research and this allowed us to initiate an NHMRC Dementia Team grant [APP1095127] to determine the earliest biological changes in asymptomatic relatives of patients. In this program we will focus on four critical core areas; 1) develop better treatment strategies, 2) confirm and further develop novel diagnostic tools, 3) identify key measurable neural traits and risk factors that are independent of pathology, and 4) understand the RNA mechanisms that underpin disease. Our resources (large, well-characterised clinical cohorts with longitudinally sampled biospecimens, animal and cell models based on protein abnormalities, international consortia) and novel techniques (clinical and imaging tools, genetics, models) will enable us to test novel treatments, develop new diagnostic and prognostic measures, and obtain new knowledge of core disease mechanisms and risks, and to better inform patient management.

Disease area:

Dementia, FTD, MND

Project - Non-Alzheimer’s disease degenerative dementias - identifying prodromal genetic/familial phenotypes and modifying factors, and protein variations involved in progression

All Chief investigators and associate investigators

• CIA Professor Glenda Halliday (UNSW/NeuRA)
• CIB Professor John Hodges (UNSW/NeuRA)
• CIC Associate Professor Simon Lewis (USyd/BMRI)
• CID Associate Professor Olivier Piguet (UNSW/NeuRA)
• CIE Professor Jillian Kril (USyd/CPC)
• CIF Associate Professor John Kwok (UNSW/NeuRA)
• CIG Associate Professor Victor Villemagne (UMelb/Austin)
• CIH Professor Matthew Kiernan (USyd/BMRI)
• CII Professor Dominic Rowe (Macquarie/Neurology)
• CIJ Professor Ian McKeith (Newcastle University, UK)

Research Project Abstract

This proposal will generate the new knowledge necessary for advancing the diagnosis of the nonAlzheimer’s disease degenerative dementias. Specifically, we have organized a team with the appropriate clinical cohorts and research skills to develop protocols that will identify the preclinical forms of frontotemporal dementia and Lewy body dementia using similar methodologies to those successfully employed to advance diagnosis of Alzheimer’s disease (Dubois et al. 2014). Importantly, our team has the capacity to translate these protocols into clinical practice and into further advances in biological knowledge that is necessary for future therapeutic targeting.

Disease area:

Dementia, FTD, PD, DLB

Project - DIPPA - FTD

All Chief investigators and associate investigators

Yolande Pijnenburg, Janine Diehl-Schmid, Daniela Galimberti, Simon Ducharme, Olivier Piguet. Glenda Halliday – Joint Collaborators

Research Project Abstract

The behavioural variant of frontotemporal dementia (bvFTD) is a common cause of early-onset dementia that presents with changes in behavior and personality. It is often misdiagnosed and mistaken for a psychiatric disorder, such as depression or bipolar disorder.

Unlike with Alzheimer’s disease we still don’t have reliable tests that enable a diagnosis of bvFTD. Recent research attention has been on hereditable forms of FTD; however, the critical challenge is how to diagnose non-familial forms of bvFTD (which accounts for 80% of all cases) early in the disease course and therefore distinguish it from late-onset psychiatric disorders that may mimic bvFTD. In this project, we will combine existing data from cohorts from several countries including clinical, neuroimaging, and blood markers combined with novel markers that were developed by the participants of the project.

We will also collect data from deceased bvFTD and psychiatric patients who had their diagnosis confirmed through pathological examination of their brains in a brain bank. We will define which of the available markers are the best predictors of the bvFTD diagnosis. We will apply the identified markers in new patient cohorts to be established and by using a statistic modeling approach, we aim to create a paradigm that enables both accurate diagnosis and prediction of the clinical course (prognosis).

Our project will contribute towards an early and accurate identification of bvFTD versus psychiatric disorders, which is crucial for appropriate management and treatment. Moreover, our results will increase the ability to predict rate of progression in non-familial bvFTD and other patients presenting with behavioral changes, that is essential for enrolment in drug trials and personalized treatments.

Disease area:

Dementia, MND, FTD, AD, PD, DLB, MSA, sleep disorders, Ageing