Lewy body dementias – Dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) - are disabling neurodegenerative conditions defined pathologically by the presence of intraneuronal α-synuclein rich aggregates (‘Lewy bodies’ and ‘Lewy neurites’). These disorders are characterized by a set of ‘core’ clinical features, namely cognitive fluctuations, visual hallucinations, motor parkinsonism, and most recently added, REM sleep behaviour disorder. These features are central to the diagnosis of Lewy bodies dementias (especially DLB) and discriminate them from other neurodegenerative disorders. Despite decades of research, the etiopathogenesis underlying Lewy body disorders is poorly understood. This accounts for the relative lack of objective biomarkers and both symptomatic and disease modifying therapies. The present thesis comprises a series of investigations that seeks to understand the phenomenology, pathophysiology, and clinical progression of Lewy body dementias through focus on each of the core clinical features. Systematic review and empiric studies are organized under the respective headings of cognitive fluctuations, visual hallucinations, REM sleep behaviour disorder, motor features, interrelationships, and clinical progression of the core features. Novel clinical and pathophysiological insights are obtained which have implications for the prediction and diagnosis of core features, the development of new objective biomarkers, and clinical endpoints of disease progression. From these studies, a shared pathophysiological basis for the core features is postulated and potential avenues for future directions are highlighted, focusing on replication and validation of new biomarkers and clinical measures, discovery of new biomarkers and mechanisms, and translation to prodromal and patient cohorts
