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Abstract
Lewy body diseases are characterized by parkinsonian disorders of movement and neuropsychiatric features of dementia, visual hallucinations and altered states of consciousness. The underlying neurobiological changes responsible for the psychiatric features are poorly understood. The integrative centre and key area for arousal, the thalamus, has not been assessed for neurodegeneration in relation to these perceptual deficits, and the brain activation patterns associated with visual hallucinations in non-demented patients have not been clearly established. This thesis aims to address these deficits in knowledge using two separate populations and methods. The first set of studies (Part one) utilizes post-mortem tissue to examine first the intralaminar and then the medial limbic thalamic nuclei across the spectrum of Lewy body diseases. Atrophy of these nuclei, atrophy of neurons, neuronal death and a-synuclein deposition were assessed and relationships with clinical variables tested. These studies found changes in several thalamic nuclei, some of which are associated with disease, and others associated with particular clinical features. Visual hallucinations, but not fluctuating consciousness, associated with atrophy of medial limbic thalamic nuclei. The second set of studies (Part two) firstly mapped cerebral blood flow in living patients with Parkinson's disease without dementia, in order to compare populations with and without visual hallucinations. A drug trial of a cholinesterase inhibitor in this population was then performed to determine clinical effect and the impact of this drug on cerebral perfusion. These studies identified occipital hypoperfusion in Parkinson's disease patients with visual hallucinations, and that increasing acetylcholine stopped the hallucinations in association with perfusion changes in limbic cortical regions. In fact, the perfusion changes in the parahippocampal and anterior cingulate cortices identified in Part two are likely to connect through the limbic thalamic relay regions identified in the clinicopathological studies of Part one. Overall, this thesis has identified that visual hallucinations are associated with subtle pathologies in a major limbic circuit in cases with Lewy body diseases. More importantly, the final set of studies suggests that anti-cholinesterase therapies can ameliorate this subtle pathological dysfunction, although further studies in larger populations are required and the cholinergic site and pathological triggers involved need to be identified.