Frontotemporal Dementia-Motor Neuron Disease: disease continuum or distinct entity?

Abstract

Frontotemporal dementia-motor neuron disease (FTD-MND) is a rare disease characterised by the simultaneous occurrence of FTD and MND. Clinical, pathological, and genetic investigations have highlighted the association between FTD and MND, but much remains unclear. The experimental studies of this thesis comprehensively and systematically investigate the natural history of cognition and behaviour in FTD-MND and explore whether FTD-MND is distinct from well-recognised FTD phenotypes using clinical, neuropsychological and multimodal neuroimaging analyses. Results arising from two separate studies (Chapters 3 and 4) reveal that the majority of FTD-MND presents with variable combinations of behaviour, language and motor deficits initially, and fulfil FTD-MND diagnosis within 24 months from symptom onset. Heterogenous deficits persist even after meeting FTD-MND diagnostic criteria. Clinical heterogeneity in FTD-MND, highlighted by using a data-driven approach, may reflect variable white matter tract involvement. Language impairment in FTD-MND is highly prevalent, and more mixed than in FTD language phenotypes. The frequency and severity of behavioural and language deficits in FTD-MND lie between that of FTD phenotypes. Over time (Chapter 5), cognition and language deficits progress more rapidly in FTD-MND than bvFTD. Progression in FTD-MND may be driven by left inferior frontal gyrus and anterior temporal lobe involvemeny. Survival in FTD-MND is much shorter than in FTD, despite a similar age at onset. Motor neuron dysfunction may be highly specific for frontotemporal lobar degeneration TAR DNA binding protein 43 kDa (FTLD-TDP, Chapter 6), but the current FTLD-TDP pathological staging scheme may not correlate with clinical progression. These findings demonstrate that FTD-MND is distinct from, rather than simply a later clinical stage of, FTD.