Project - Towards treatments for non-Alzheimer neurodegenerative diseases by establishing their biology at all disease stages
All Chief investigators and associate investigators
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).